Adrb1 encodes the beta-1 adrenergic receptor, a class A (rhodopsin-like) seven-transmembrane G protein-coupled receptor for the catecholamines norepinephrine and epinephrine. At the plasma membrane it couples to Gs to stimulate adenylyl cyclase, raising cAMP and activating protein kinase A, which phosphorylates targets such as L-type Ca2+ channels. A C-terminal class I PDZ ligand (E-S-K-V) binds scaffolds including MAGI-2, MAGI-3, PSD-95, GOPC and the cAMP-dependent Ras exchange factor RAPGEF2 (CNrasGEF), which shapes receptor trafficking and couples cAMP to Ras activation. After agonist stimulation the receptor is phosphorylated, internalized through early endosomes and recycled. Beta1 is the predominant beta-adrenoceptor of the heart, where it mediates sympathetic increases in heart rate and contractile force, and its chronic stimulation drives cardiomyocyte hypertrophy and apoptosis. Outside the heart it contributes to sympathetic activation of brown-fat thermogenesis, and in the brain (cortex, hippocampus, amygdala, pons) it modulates synaptic plasticity, memory retrieval and sleep/wake behaviour.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001996 positive regulation of heart rate by epinephrine-norepinephrine | ISO GO_REF:0000121 | ACCEPT | Summary: Beta1-AR mediates the sympathetic catecholamine-driven increase in heart rate; core physiological role. Reason: Donor mouse Adrb1-null hearts lack the chronotropic response to beta agonists and double-knockout analysis attributes beta-agonist chronotropy almost exclusively to beta1. Rat pharmacology agrees (atenolol bradycardia, PMID:9089896). This is the principal physiological output of the receptor. Supporting Evidence: PMID:8693001 Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered PMID:10358009 beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR) PMID:9089896 beta 1-adrenergic receptor blockade with atenolol (Aten) lowered pre-exercise fH and (fHmax) to comparable values in A and in NA rats |
| GO:0001996 positive regulation of heart rate by epinephrine-norepinephrine | ISO GO_REF:0000121 | ACCEPT | Summary: Beta1-AR mediates the sympathetic catecholamine-driven increase in heart rate; core physiological role. Reason: Donor mouse Adrb1-null hearts lack the chronotropic response to beta agonists and double-knockout analysis attributes beta-agonist chronotropy almost exclusively to beta1. Rat pharmacology agrees (atenolol bradycardia, PMID:9089896). This is the principal physiological output of the receptor. Supporting Evidence: PMID:8693001 Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered PMID:10358009 beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR) PMID:9089896 beta 1-adrenergic receptor blockade with atenolol (Aten) lowered pre-exercise fH and (fHmax) to comparable values in A and in NA rats |
| GO:0001997 positive regulation of the force of heart contraction by epinephrine-norepinephrine | IEA GO_REF:0000117 | ACCEPT | Summary: Beta1-AR mediates the catecholamine-driven increase in cardiac contractile force (positive inotropy); core physiological role. Reason: Mouse knockouts lose the inotropic response to beta agonists; in rat atria and ventricle the noradrenaline inotropic effect runs through beta1 (PMID:19133992). UniProt (curated) describes beta1 stimulation of cardiomyocyte contraction. Supporting Evidence: PMID:8693001 Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered PMID:10358009 beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR) PMID:19133992 PDE4 blunts the beta(1)-adrenoceptor-mediated inotropic effects. UniProtKB:P18090 plays a role in the physiologic regulation of cardiac functions such as stimulation of cardiomyocyte contraction |
| GO:0001997 positive regulation of the force of heart contraction by epinephrine-norepinephrine | ISO GO_REF:0000121 | ACCEPT | Summary: Beta1-AR mediates the catecholamine-driven increase in cardiac contractile force (positive inotropy); core physiological role. Reason: Mouse knockouts lose the inotropic response to beta agonists; in rat atria and ventricle the noradrenaline inotropic effect runs through beta1 (PMID:19133992). UniProt (curated) describes beta1 stimulation of cardiomyocyte contraction. Supporting Evidence: PMID:8693001 Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered PMID:10358009 beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR) PMID:19133992 PDE4 blunts the beta(1)-adrenoceptor-mediated inotropic effects. UniProtKB:P18090 plays a role in the physiologic regulation of cardiac functions such as stimulation of cardiomyocyte contraction |
| GO:0002024 diet induced thermogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1-AR is required for diet-induced thermogenesis in mouse brown fat; non-core physiological role. Reason: Beta1-knockout mice fail to develop diet-induced thermogenesis (PMID:22728333), consistent with the beta-less mouse (PMID:12161655). The receptor acts upstream as the sympathetic signal transducer in brown adipocytes; the thermogenic process is downstream, so the term is kept as non-core. Supporting Evidence: PMID:22728333 Ξ²(1)KO mice were more susceptible to obesity than WT controls and failed to develop diet-induced thermogenesis PMID:12161655 These findings establish that betaARs are necessary for diet-induced thermogenesis |
| GO:0002025 norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Beta1-AR contributes modestly to catecholamine-mediated vasodilation; vascular relaxation is shared with beta2/beta3. Reason: Knockout analysis attributes vascular relaxation to all three beta-AR subtypes, not predominantly beta1 (PMID:10358009). The IBA node (PTN002798485) is the ADRB1 subfamily seeded by mouse Adrb1; the rat protein is inside that clade, so the inheritance is sound, but the process is peripheral to the cardiac core role. Supporting Evidence: PMID:10358009 beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR) |
| GO:0002025 norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1-AR contributes modestly to catecholamine-mediated vasodilation; vascular relaxation is shared with beta2/beta3. Reason: Knockout analysis attributes vascular relaxation to all three beta-AR subtypes, not predominantly beta1 (PMID:10358009). The IBA node (PTN002798485) is the ADRB1 subfamily seeded by mouse Adrb1; the rat protein is inside that clade, so the inheritance is sound, but the process is peripheral to the cardiac core role. Supporting Evidence: PMID:10358009 beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR) |
| GO:0003061 positive regulation of the force of heart contraction by norepinephrine | IDA PMID:19133992 Inotropy and L-type Ca2+ current, activated by beta1- and be... | ACCEPT | Summary: Noradrenaline increases rat atrial and ventricular force through beta1-AR. Reason: Christ et al. separated beta1 (noradrenaline + ICI118551) from beta2 responses in rat cardiac tissue; beta1 mediated the inotropic effect, modulated by PDE4. Direct rat evidence for the core cardiac role. Supporting Evidence: PMID:19133992 PDE4 blunts the beta(1)-adrenoceptor-mediated inotropic effects. |
| GO:0003084 positive regulation of systemic arterial blood pressure | IMP PMID:18931026 Effect of stellate ganglionectomy on basal cardiovascular fu... | KEEP AS NON CORE | Summary: Chronic beta1 blockade with atenolol lowers mean arterial pressure in rats. Reason: Pharmacological loss-of-function supports a role in maintaining arterial pressure, largely via cardiac output (and renal renin release, not assayed here). Systemic blood pressure is an organismal outcome downstream of the receptor's cardiac role, so non-core. Supporting Evidence: PMID:18931026 Five days of atenolol treatment decreased MAP similarly in SGX and Sham rats. |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Correct but general parent of beta1-adrenergic receptor activity. Reason: The rat receptor shows a beta1 pharmacological profile when expressed (PMID:1695899) and the gene already carries GO:0004940 beta1-adrenergic receptor activity by IDA/IBA; this parent term should be refined to that descendant. Proposed replacements: beta1-adrenergic receptor activity Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0004935 adrenergic receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Correct but general parent of beta1-adrenergic receptor activity. Reason: The rat receptor shows a beta1 pharmacological profile when expressed (PMID:1695899) and the gene already carries GO:0004940 beta1-adrenergic receptor activity by IDA/IBA; this parent term should be refined to that descendant. Proposed replacements: beta1-adrenergic receptor activity Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0004939 beta-adrenergic receptor activity | IEA GO_REF:0000117 | MODIFY | Summary: Correct but general parent of beta1-adrenergic receptor activity. Reason: The rat receptor shows a beta1 pharmacological profile when expressed (PMID:1695899) and the gene already carries GO:0004940 beta1-adrenergic receptor activity by IDA/IBA; this parent term should be refined to that descendant. Proposed replacements: beta1-adrenergic receptor activity Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0004940 beta1-adrenergic receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function: Gs-coupled beta1-adrenergic receptor activity. Reason: Expressed rat Adrb1 binds beta ligands and stimulates adenylyl cyclase with the beta1 agonist rank order (PMID:1695899); native rat beta1 in chromaffin cells potentiates L-type Ca2+ current via PKA (PMID:12514203); mouse knockouts lose cardiac AC stimulation (PMID:8693001). IBA node placement in the ADRB1 clade is consistent. Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:12514203 suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs PMID:8693001 this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0004940 beta1-adrenergic receptor activity | IDA PMID:12514203 Opposite action of beta1- and beta2-adrenergic receptors on ... | ACCEPT | Summary: Core molecular function: Gs-coupled beta1-adrenergic receptor activity. Reason: Expressed rat Adrb1 binds beta ligands and stimulates adenylyl cyclase with the beta1 agonist rank order (PMID:1695899); native rat beta1 in chromaffin cells potentiates L-type Ca2+ current via PKA (PMID:12514203); mouse knockouts lose cardiac AC stimulation (PMID:8693001). IBA node placement in the ADRB1 clade is consistent. Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:12514203 suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs PMID:8693001 this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0004940 beta1-adrenergic receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Core molecular function: Gs-coupled beta1-adrenergic receptor activity. Reason: Expressed rat Adrb1 binds beta ligands and stimulates adenylyl cyclase with the beta1 agonist rank order (PMID:1695899); native rat beta1 in chromaffin cells potentiates L-type Ca2+ current via PKA (PMID:12514203); mouse knockouts lose cardiac AC stimulation (PMID:8693001). IBA node placement in the ADRB1 clade is consistent. Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:12514203 suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs PMID:8693001 this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0004940 beta1-adrenergic receptor activity | ISO GO_REF:0000121 | ACCEPT | Summary: Core molecular function: Gs-coupled beta1-adrenergic receptor activity. Reason: Expressed rat Adrb1 binds beta ligands and stimulates adenylyl cyclase with the beta1 agonist rank order (PMID:1695899); native rat beta1 in chromaffin cells potentiates L-type Ca2+ current via PKA (PMID:12514203); mouse knockouts lose cardiac AC stimulation (PMID:8693001). IBA node placement in the ADRB1 clade is consistent. Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:12514203 suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs PMID:8693001 this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0004940 beta1-adrenergic receptor activity | ISO GO_REF:0000121 | ACCEPT | Summary: Core molecular function: Gs-coupled beta1-adrenergic receptor activity. Reason: Expressed rat Adrb1 binds beta ligands and stimulates adenylyl cyclase with the beta1 agonist rank order (PMID:1695899); native rat beta1 in chromaffin cells potentiates L-type Ca2+ current via PKA (PMID:12514203); mouse knockouts lose cardiac AC stimulation (PMID:8693001). IBA node placement in the ADRB1 clade is consistent. Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:12514203 suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs PMID:8693001 this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0004940 beta1-adrenergic receptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Core molecular function: Gs-coupled beta1-adrenergic receptor activity. Reason: Expressed rat Adrb1 binds beta ligands and stimulates adenylyl cyclase with the beta1 agonist rank order (PMID:1695899); native rat beta1 in chromaffin cells potentiates L-type Ca2+ current via PKA (PMID:12514203); mouse knockouts lose cardiac AC stimulation (PMID:8693001). IBA node placement in the ADRB1 clade is consistent. Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:12514203 suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs PMID:8693001 this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0005515 protein binding | IPI PMID:16316992 Proteomic analysis of beta1-adrenergic receptor interactions... | MODIFY | Summary: Interaction with MAGI-3 is via the receptor's C-terminal PDZ ligand binding MAGI-3 PDZ1. Reason: Bare protein binding is uninformative. The cited study maps the interaction to the receptor's E-S-K-V C-terminus binding the first PDZ domain of MAGI-3 (V466A abolishes it), so PDZ domain binding captures the function. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:16316992 The beta1AR carboxyl terminus was found to bind specifically to the first PDZ domain of MAGI-3, with the last four amino acids (E-S-K-V) of beta1AR being the key determinants of the interaction. |
| GO:0005769 early endosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1-AR transits early endosomes during agonist-induced endocytosis and recycling. Reason: Curated UniProt text and trafficking studies show agonist-induced internalization and recycling of beta1-AR to the plasma membrane; endosomal residence is a trafficking intermediate, not where signalling function is primarily executed. Supporting Evidence: UniProtKB:P18090 Localized to early endosomes during endocytic trafficking PMID:21540189 Like Ξ²1AR, which recycles to the plasma membrane, GPER co-traffics with transferrin+, Rab11+ recycling endosomes. |
| GO:0005769 early endosome | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Beta1-AR transits early endosomes during agonist-induced endocytosis and recycling. Reason: Curated UniProt text and trafficking studies show agonist-induced internalization and recycling of beta1-AR to the plasma membrane; endosomal residence is a trafficking intermediate, not where signalling function is primarily executed. Supporting Evidence: UniProtKB:P18090 Localized to early endosomes during endocytic trafficking PMID:21540189 Like Ξ²1AR, which recycles to the plasma membrane, GPER co-traffics with transferrin+, Rab11+ recycling endosomes. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane is the site of ligand binding and G protein activation. Reason: Seven-TM GPCR; rat beta1 colocalizes with CNrasGEF at the plasma membrane (PMID:12391161), which is the IDA. IBA across adrenergic/aminergic receptors is consistent. Supporting Evidence: PMID:12391161 a substantial fraction of CNrasGEF colocalizes with the Ξ²1-AR at the plasma membrane in HEK-293T cells UniProtKB:P18090 Localized at the plasma membrane |
| GO:0005886 plasma membrane | IDA PMID:12391161 Direct binding of the beta1 adrenergic receptor to the cycli... | ACCEPT | Summary: Plasma membrane is the site of ligand binding and G protein activation. Reason: Seven-TM GPCR; rat beta1 colocalizes with CNrasGEF at the plasma membrane (PMID:12391161), which is the IDA. IBA across adrenergic/aminergic receptors is consistent. Supporting Evidence: PMID:12391161 a substantial fraction of CNrasGEF colocalizes with the Ξ²1-AR at the plasma membrane in HEK-293T cells UniProtKB:P18090 Localized at the plasma membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane is the site of ligand binding and G protein activation. Reason: Seven-TM GPCR; rat beta1 colocalizes with CNrasGEF at the plasma membrane (PMID:12391161), which is the IDA. IBA across adrenergic/aminergic receptors is consistent. Supporting Evidence: PMID:12391161 a substantial fraction of CNrasGEF colocalizes with the Ξ²1-AR at the plasma membrane in HEK-293T cells UniProtKB:P18090 Localized at the plasma membrane |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Plasma membrane is the site of ligand binding and G protein activation. Reason: Seven-TM GPCR; rat beta1 colocalizes with CNrasGEF at the plasma membrane (PMID:12391161), which is the IDA. IBA across adrenergic/aminergic receptors is consistent. Supporting Evidence: PMID:12391161 a substantial fraction of CNrasGEF colocalizes with the Ξ²1-AR at the plasma membrane in HEK-293T cells UniProtKB:P18090 Localized at the plasma membrane |
| GO:0005980 glycogen catabolic process | IDA PMID:17911346 Greater glycogen utilization during 1- than 2-adrenergic rec... | MODIFY | Summary: Beta1 stimulation drives glycogenolysis in perfused rat heart; the receptor regulates rather than performs glycogen breakdown. Reason: The receptor does not catalyse glycogen catabolism; it promotes it through cAMP/PKA activation of phosphorylase kinase. The observation supports positive regulation of glycogen catabolic process (non-core metabolic output). Proposed replacements: positive regulation of glycogen catabolic process Supporting Evidence: PMID:17911346 The greater glycogenolysis was observed during beta(1)- than beta(2)-AR stimulation |
| GO:0007186 G protein-coupled receptor signaling pathway | IDA PMID:12514203 Opposite action of beta1- and beta2-adrenergic receptors on ... | MODIFY | Summary: Correct but general; the specific pathway is adenylate cyclase-activating adrenergic receptor signaling. Reason: Rat beta1 couples to Gs and adenylyl cyclase (PMID:1695899; PMID:12514203). The gene already carries GO:0071880, a descendant of this term. Proposed replacements: adenylate cyclase-activating adrenergic receptor signaling pathway Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:12514203 suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: Correct but general; the specific pathway is adenylate cyclase-activating adrenergic receptor signaling. Reason: Rat beta1 couples to Gs and adenylyl cyclase (PMID:1695899; PMID:12514203). The gene already carries GO:0071880, a descendant of this term. Proposed replacements: adenylate cyclase-activating adrenergic receptor signaling pathway Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:12514203 suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: Correct but general; the specific pathway is adenylate cyclase-activating adrenergic receptor signaling. Reason: Beta1 activates adenylyl cyclase via Gs (PMID:1695899; knockout PMID:8693001). GO:0071880 is the is_a descendant specific to adrenergic receptors and is already annotated. Proposed replacements: adenylate cyclase-activating adrenergic receptor signaling pathway Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:8693001 this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | ISO GO_REF:0000121 | MODIFY | Summary: Correct but general; the specific pathway is adenylate cyclase-activating adrenergic receptor signaling. Reason: Beta1 activates adenylyl cyclase via Gs (PMID:1695899; knockout PMID:8693001). GO:0071880 is the is_a descendant specific to adrenergic receptors and is already annotated. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:87937 SUPPORTS TRANSFER Mouse IMP (PMID:8693001) shows loss of cardiac adenylyl cyclase stimulation in beta1-null mice; transfer is sound, the term is just less specific than GO:0071880. Proposed replacements: adenylate cyclase-activating adrenergic receptor signaling pathway Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:8693001 this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice |
| GO:0007266 Rho protein signal transduction | IMP PMID:18306009 High concentrations of landiolol, a beta(1)-adrenoceptor ant... | MARK AS OVER ANNOTATED | Summary: Rho-kinase-dependent tracheal contraction caused by 700 microM landiolol; not shown to be beta1-mediated. Reason: The effect requires concentrations orders of magnitude above landiolol's beta1 affinity, and the abstract gives no evidence (e.g. block by another beta1 ligand, or receptor knockdown) that the Rho-kinase response is mediated by Adrb1; airway smooth muscle tone is classically beta2-regulated. Experimental row, abstract only: flagged for expert check rather than removed. Supporting Evidence: PMID:18306009 high concentrations of landiolol could cause airway smooth muscle contraction through the Rho-kinase pathway |
| GO:0007613 memory | IMP PMID:17961922 Down-regulation of beta1-adrenoceptors gene expression by sh... | KEEP AS NON CORE | Summary: Beta1-AR in basolateral amygdala/hippocampus is required for memory retrieval; non-core neural role. Reason: siRNA knockdown of beta1 in rat BLA impairs auditory fear memory retrieval, matching mouse evidence that hippocampal beta1 signalling is required for retrieval (PMID:15066288). A neuromodulatory output of the receptor. Supporting Evidence: PMID:17961922 memory retrieval was impaired as beta(1)-AR protein expression was prevented PMID:15066288 The role of norepinephrine in retrieval requires signaling through the beta(1)-adrenergic receptor in the hippocampus. |
| GO:0009409 response to cold | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1-AR is needed for normal thermoregulation in the cold; non-core. Reason: Beta1-KO mice become hypothermic during cold exposure (PMID:22728333); the triple-KO donor evidence (PMID:12387862) is less specific. Kept as non-core physiological role. Supporting Evidence: PMID:22728333 developed hypothermia during cold exposure PMID:12387862 Hence, beta-adrenergic signalling is essential for the resistance to obesity and cold |
| GO:0010460 positive regulation of heart rate | IMP PMID:9089896 Role of beta-adrenergic and cholinergic systems in acclimati... | MODIFY | Summary: Beta1 blockade lowers heart rate in rats; correct but less specific than the epinephrine-norepinephrine term. Reason: The heart-rate effect of beta1 is the sympathetic catecholamine route, captured by GO:0001996 (an is_a descendant already on the gene). Proposed replacements: positive regulation of heart rate by epinephrine-norepinephrine Supporting Evidence: PMID:9089896 beta 1-adrenergic receptor blockade with atenolol (Aten) lowered pre-exercise fH and (fHmax) to comparable values in A and in NA rats PMID:8693001 Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered |
| GO:0010666 positive regulation of cardiac muscle cell apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1 (but not beta2) stimulation induces cardiomyocyte apoptosis; non-core pathophysiological role. Reason: Adenoviral re-expression of beta1 in beta1/beta2-null mouse myocytes induces apoptosis on stimulation (PMID:11171998); rat beta1 siRNA reduces myocyte apoptosis after MI (PMID:17143192). Real, but a consequence of chronic signalling rather than the receptor's evolved role. Supporting Evidence: PMID:11171998 Stimulation of beta(1)-AR, but not beta(2)-AR, markedly induced myocyte apoptosis PMID:17143192 The protective mechanism involved reduction of cardiomyocyte apoptosis in the beta1 siRNA-treated hearts. UniProtKB:P18090 Also delivers proapoptotic signals in cardiomyocytes |
| GO:0010666 positive regulation of cardiac muscle cell apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Beta1 (but not beta2) stimulation induces cardiomyocyte apoptosis; non-core pathophysiological role. Reason: Adenoviral re-expression of beta1 in beta1/beta2-null mouse myocytes induces apoptosis on stimulation (PMID:11171998); rat beta1 siRNA reduces myocyte apoptosis after MI (PMID:17143192). Real, but a consequence of chronic signalling rather than the receptor's evolved role. Supporting Evidence: PMID:11171998 Stimulation of beta(1)-AR, but not beta(2)-AR, markedly induced myocyte apoptosis PMID:17143192 The protective mechanism involved reduction of cardiomyocyte apoptosis in the beta1 siRNA-treated hearts. UniProtKB:P18090 Also delivers proapoptotic signals in cardiomyocytes |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Correct but general; the receptor is in the plasma membrane. Reason: Seven-TM receptor localized at the plasma membrane (PMID:12391161); the gene already carries GO:0005886. Proposed replacements: plasma membrane Supporting Evidence: PMID:12391161 a substantial fraction of CNrasGEF colocalizes with the Ξ²1-AR at the plasma membrane in HEK-293T cells UniProtKB:P18090 Localized at the plasma membrane |
| GO:0016020 membrane | ISO GO_REF:0000121 | MODIFY | Summary: Correct but general; the receptor is in the plasma membrane. Reason: Seven-TM receptor localized at the plasma membrane (PMID:12391161); the gene already carries GO:0005886. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:87937 SUPPORTS TRANSFER Mouse membrane annotation (PMID:8693001, knockout allele) is correct but generic; the receptor is in the plasma membrane. Proposed replacements: plasma membrane Supporting Evidence: PMID:12391161 a substantial fraction of CNrasGEF colocalizes with the Ξ²1-AR at the plasma membrane in HEK-293T cells UniProtKB:P18090 Localized at the plasma membrane |
| GO:0030165 PDZ domain binding | ISO GO_REF:0000121 | ACCEPT | Summary: The C-terminal E-S-K-V PDZ ligand binds PDZ domains of MAGI-2/3, PSD-95, GOPC, SAP97 and RAPGEF2. Reason: Directly shown for rat beta1 with MAGI-3 (PMID:16316992) and CNrasGEF/RAPGEF2 (PMID:12391161), and for human beta1 with MAGI-2 (PMID:11526121). These interactions set receptor trafficking and route cAMP to Ras activation, a beta1-specific feature. Supporting Evidence: PMID:16316992 The beta1AR carboxyl terminus was found to bind specifically to the first PDZ domain of MAGI-3, with the last four amino acids (E-S-K-V) of beta1AR being the key determinants of the interaction. PMID:12391161 The beta1 adrenergic receptor (beta1-AR) binds to the PDZ domain of the cyclic AMP (cAMP)-dependent Ras exchange factor, CNrasGEF, via its C-terminal SkV motif. PMID:11526121 The beta1AR carboxyl terminus binds with high affinity to the first PDZ domain of MAGI-2 UniProtKB:P18090 Interacts (via PDZ-binding motif) with GOPC, MAGI3 and DLG4; interaction mediates ADRB1 trafficking and signaling in a cell-specific manner |
| GO:0031649 heat generation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1-AR mediates sympathetic stimulation of brown-fat heat production; non-core. Reason: Beta1-KO mice have reduced interscapular BAT thermal response to norepinephrine or dobutamine (PMID:22728333). Downstream physiological output. Supporting Evidence: PMID:22728333 the Ξ²(1) signaling pathway mediates most of the SNS stimulation of adaptive thermogenesis |
| GO:0031694 alpha-2A adrenergic receptor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1-AR heterodimerizes with the alpha2A-adrenergic receptor (human data). Reason: Co-immunoprecipitation and altered pharmacology in HEK-293 cells (PMID:12529373) support the interaction; its physiological significance is uncertain, so non-core. Supporting Evidence: PMID:12529373 We have found that the beta(1)-adrenergic receptor (beta(1)AR) and alpha(2A)-adrenergic receptor (alpha(2A)AR) heterodimerize when coexpressed in cells. |
| GO:0035811 negative regulation of urine volume | IDA PMID:7912752 Effects of beta 1- and beta 2-adrenoceptor agonists applied ... | MARK AS OVER ANNOTATED | Summary: PVN-applied beta agonists reduce urine output, but the study attributes antidiuresis mainly to beta2. Reason: Beta1-selective agonists were much weaker than fenoterol/isoproterenol and the authors conclude beta2 receptors predominate; the ARBA IEA row restates the same claim. A beta1 contribution was not excluded in normotensive strains, so this is over-annotation rather than a contradicted function. Flagged for expert check. Supporting Evidence: PMID:7912752 It was suggested that there were predominantly beta 2-adrenoceptors mediating antidiuresis in SHR. |
| GO:0035811 negative regulation of urine volume | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: PVN-applied beta agonists reduce urine output, but the study attributes antidiuresis mainly to beta2. Reason: Beta1-selective agonists were much weaker than fenoterol/isoproterenol and the authors conclude beta2 receptors predominate; the ARBA IEA row restates the same claim. A beta1 contribution was not excluded in normotensive strains, so this is over-annotation rather than a contradicted function. Flagged for expert check. Supporting Evidence: PMID:7912752 It was suggested that there were predominantly beta 2-adrenoceptors mediating antidiuresis in SHR. |
| GO:0040015 negative regulation of multicellular organism growth | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Derived from beta1/beta2/beta3 triple-knockout obesity; not attributable to beta1 nor a growth-regulation function. Reason: The donor IGI is the triple-KO mouse that is obese and cold-sensitive (PMID:12387862); increased adiposity is not negative regulation of organism growth by beta1, and the phenotype cannot be apportioned to beta1. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: MGI:MGI:87937 SOURCE WEAK OR INFERRED Donor IGI rests on beta1/beta2/beta3 triple-knockout obesity (PMID:12387862), which cannot be apportioned to beta1 and is not regulation of growth. Supporting Evidence: PMID:12387862 Hence, beta-adrenergic signalling is essential for the resistance to obesity and cold |
| GO:0042596 fear response | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1 signalling in hippocampus/amygdala is needed for retrieval of fear-conditioned memories; non-core. Reason: Mouse donor (PMID:15066288) shows retrieval of contextual fear memory requires hippocampal beta1; rat BLA knockdown impairs auditory fear memory retrieval (PMID:17961922). Supporting Evidence: PMID:15066288 The role of norepinephrine in retrieval requires signaling through the beta(1)-adrenergic receptor in the hippocampus. PMID:17961922 memory retrieval was impaired as beta(1)-AR protein expression was prevented |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000117 | MODIFY | Summary: Beta1 promotes apoptosis specifically in cardiomyocytes; the specific term is already on the gene. Reason: Evidence (rat siRNA after MI; mouse myocyte re-expression) concerns cardiomyocyte apoptosis, so the general term should be refined to GO:0010666. Proposed replacements: positive regulation of cardiac muscle cell apoptotic process Supporting Evidence: PMID:17143192 The protective mechanism involved reduction of cardiomyocyte apoptosis in the beta1 siRNA-treated hearts. PMID:11171998 Stimulation of beta(1)-AR, but not beta(2)-AR, markedly induced myocyte apoptosis |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:17143192 Specific beta1-adrenergic receptor silencing with small inte... | MODIFY | Summary: Beta1 promotes apoptosis specifically in cardiomyocytes; the specific term is already on the gene. Reason: Evidence (rat siRNA after MI; mouse myocyte re-expression) concerns cardiomyocyte apoptosis, so the general term should be refined to GO:0010666. Proposed replacements: positive regulation of cardiac muscle cell apoptotic process Supporting Evidence: PMID:17143192 The protective mechanism involved reduction of cardiomyocyte apoptosis in the beta1 siRNA-treated hearts. PMID:11171998 Stimulation of beta(1)-AR, but not beta(2)-AR, markedly induced myocyte apoptosis |
| GO:0043176 amine binding | IPI PMID:6289140 Analysis of the beta 1 and beta 2 adrenoceptor interactions ... | KEEP AS NON CORE | Summary: Rat beta1-AR binds the amine partial agonist clenbuterol with nanomolar affinity. Reason: Pharmacological binding of a synthetic amine ligand (KD 38 nM) in rat atria. True, and no more specific binding term fits a drug ligand; the physiologically relevant ligand binding is part of GO:0004940. Non-core. Supporting Evidence: PMID:6289140 Equilibrium dissociation constants were 38 and 6.3 nM for beta 1 and beta 2 adrenoceptors, respectively. |
| GO:0045187 regulation of circadian sleep/wake cycle, sleep | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1-AR signalling in dorsal pons neurons regulates sleep/wake; a human short-sleep variant and knock-in mice sleep less. Reason: Well supported by human genetics and knock-in mice (PMID:31473062), and curated in UniProt. A neural output of the receptor, so non-core. Note that the donor IMP rows cite PMID:25083013, a BHLHE41 paper (see source_defects). Supporting Evidence: PMID:31473062 We have identified a mutation in the Ξ²1-adrenergic receptor gene in humans who require fewer hours of sleep than most. PMID:31473062 In vivo, the mice carrying the same mutation demonstrated short sleep behavior. UniProtKB:P18090 Involved in the regulation of sleep/wake behaviors |
| GO:0045187 regulation of circadian sleep/wake cycle, sleep | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1-AR signalling in dorsal pons neurons regulates sleep/wake; a human short-sleep variant and knock-in mice sleep less. Reason: Well supported by human genetics and knock-in mice (PMID:31473062), and curated in UniProt. A neural output of the receptor, so non-core. Note that the donor IMP rows cite PMID:25083013, a BHLHE41 paper (see source_defects). Supporting Evidence: PMID:31473062 We have identified a mutation in the Ξ²1-adrenergic receptor gene in humans who require fewer hours of sleep than most. PMID:31473062 In vivo, the mice carrying the same mutation demonstrated short sleep behavior. UniProtKB:P18090 Involved in the regulation of sleep/wake behaviors |
| GO:0045187 regulation of circadian sleep/wake cycle, sleep | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Beta1-AR signalling in dorsal pons neurons regulates sleep/wake; a human short-sleep variant and knock-in mice sleep less. Reason: Well supported by human genetics and knock-in mice (PMID:31473062), and curated in UniProt. A neural output of the receptor, so non-core. Note that the donor IMP rows cite PMID:25083013, a BHLHE41 paper (see source_defects). Supporting Evidence: PMID:31473062 We have identified a mutation in the Ξ²1-adrenergic receptor gene in humans who require fewer hours of sleep than most. PMID:31473062 In vivo, the mice carrying the same mutation demonstrated short sleep behavior. UniProtKB:P18090 Involved in the regulation of sleep/wake behaviors |
| GO:0045823 positive regulation of heart contraction | IEA GO_REF:0000002 | MODIFY | Summary: Correct but general; beta1 raises both heart rate and contractile force via catecholamines. Reason: Both specific descendants are already annotated and supported (PMID:8693001; PMID:10358009). Proposed replacements: positive regulation of heart rate by epinephrine-norepinephrine positive regulation of the force of heart contraction by epinephrine-norepinephrine Supporting Evidence: PMID:8693001 Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered PMID:10358009 beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR) |
| GO:0045986 negative regulation of smooth muscle contraction | IMP PMID:18306009 High concentrations of landiolol, a beta(1)-adrenoceptor ant... | MARK AS OVER ANNOTATED | Summary: Inferred from landiolol-induced tracheal contraction at 700 microM; not shown to be beta1-mediated. Reason: The contraction occurred at concentrations far above beta1 affinity and proceeded through Rho-kinase; nothing in the abstract shows that it reflects loss of beta1 tone. Airway relaxation is classically beta2. Flagged for expert check. Supporting Evidence: PMID:18306009 high concentrations of landiolol could cause airway smooth muscle contraction through the Rho-kinase pathway |
| GO:0046982 protein heterodimerization activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Heterodimerization with alpha2A-AR (human data). Reason: Supported by co-IP and agonist-induced co-internalization (PMID:12529373); physiological significance uncertain. Supporting Evidence: PMID:12529373 We have found that the beta(1)-adrenergic receptor (beta(1)AR) and alpha(2A)-adrenergic receptor (alpha(2A)AR) heterodimerize when coexpressed in cells. |
| GO:0048639 positive regulation of developmental growth | IEA GO_REF:0000117 | MODIFY | Summary: Reflects beta1-driven cardiomyocyte hypertrophic growth; the specific term is already on the gene. Reason: Beta1 is the main beta-AR subtype driving cardiomyocyte hypertrophy (PMID:18194989). GO:0061051 is an is_a descendant of this ARBA term. Proposed replacements: positive regulation of cell growth involved in cardiac muscle cell development Supporting Evidence: PMID:18194989 Cardiac hypertrophy by activation of the beta-adrenergic receptor (beta AR) is mediated more efficiently by the beta1-AR than by the beta2-AR. |
| GO:0050873 brown fat cell differentiation | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Derived from triple-knockout brown-fat morphology; not shown for beta1 alone. Reason: The donor IGI is the beta1/2/3 triple knockout (PMID:12387862) with abnormal brown fat; beta1-specific contribution to brown adipocyte differentiation is not demonstrated in that study. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: MGI:MGI:87937 SOURCE WEAK OR INFERRED Donor IGI rests on abnormal brown fat in the triple beta-AR knockout (PMID:12387862); no beta1-specific differentiation data. Supporting Evidence: PMID:12387862 Hence, beta-adrenergic signalling is essential for the resistance to obesity and cold |
| GO:0051241 negative regulation of multicellular organismal process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Very broad ARBA term with no specific supported child on this gene. Reason: The term carries little information, and the only plausible negative-regulation children on this gene (urine volume, smooth muscle contraction) are themselves over-annotations. Supporting Evidence: PMID:7912752 It was suggested that there were predominantly beta 2-adrenoceptors mediating antidiuresis in SHR. |
| GO:0051924 regulation of calcium ion transport | IDA PMID:19133992 Inotropy and L-type Ca2+ current, activated by beta1- and be... | MODIFY | Summary: Noradrenaline via beta1 increases L-type Ca2+ current in rat cardiomyocytes; refine to the specific term already on the gene. Reason: The observed effect is an increase in L-type Ca2+ current (influx), which GO:1905665 captures more precisely. Proposed replacements: positive regulation of calcium ion import across plasma membrane Supporting Evidence: PMID:19133992 Both rolipram and cilostamide augmented the (-)-noradrenaline (1 micromol x L(-1)) evoked increase in I(Ca-L). PMID:12514203 suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs |
| GO:0055088 lipid homeostasis | IMP PMID:22457517 Role of Ξ²-adrenergic receptors in regulation of hepatic fat ... | KEEP AS NON CORE | Summary: Overexpression of beta1 in hepatocytes increases lipid content; non-core. Reason: Gain-of-function in cultured hepatocytes, shared with beta2; consistent with the steatosis of beta1-KO mice on high-fat diet (PMID:22728333) but indirect. Supporting Evidence: PMID:22457517 in vitro overexpression of Ξ²1- and Ξ²2-AR subtypes in hepatocytes from young rodents increased cellular lipid content |
| GO:0060080 inhibitory postsynaptic potential | IMP PMID:18262504 Labetalol facilitates GABAergic transmission to rat periaque... | MARK AS OVER ANNOTATED | Summary: Beta1 blockade increases presynaptic GABA release onto PAG neurons; beta1 is not part of the postsynaptic potential. Reason: The study locates the beta1 effect presynaptically (sIPSC frequency, not amplitude, changes). Beta1 restrains GABA release; it does not generate the inhibitory postsynaptic potential. At most a presynaptic modulation of synaptic transmission. Supporting Evidence: PMID:18262504 Metoprolol, a specific beta1-adrenoceptor antagonist, also reversibly enhanced sIPSC frequency. PMID:18262504 labetalol enhances GABAergic synaptic transmission by a presynaptic mechanism |
| GO:0061051 positive regulation of cell growth involved in cardiac muscle cell development | IMP PMID:18194989 Endocytosis machinery is required for beta1-adrenergic recep... | KEEP AS NON CORE | Summary: Beta1-AR drives cardiomyocyte hypertrophy via endocytosis/Src/Akt; non-core. Reason: Rat neonatal cardiomyocyte data show beta1 is more effective than beta2 at inducing hypertrophy. A pathophysiological downstream output. Supporting Evidence: PMID:18194989 Cardiac hypertrophy by activation of the beta-adrenergic receptor (beta AR) is mediated more efficiently by the beta1-AR than by the beta2-AR. |
| GO:0071880 adenylate cyclase-activating adrenergic receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Core process: Gs/adenylyl cyclase-coupled adrenergic signalling. Reason: Rat beta1 stimulates adenylyl cyclase when expressed (PMID:1695899), is coupled to AC in native pituitary cells (PMID:18202135), and mouse knockouts lose cardiac AC stimulation (PMID:8693001). IBA node PTN001205212 covers beta-adrenergic receptors and is sound. Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:18202135 The present data suggest that beta(1)-AR in the anterior pituitary is positively coupled to adenylyl cyclase but is constitutively active in a pertussis toxin-sensitive manner. PMID:8693001 this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0071880 adenylate cyclase-activating adrenergic receptor signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: Core process: Gs/adenylyl cyclase-coupled adrenergic signalling. Reason: Rat beta1 stimulates adenylyl cyclase when expressed (PMID:1695899), is coupled to AC in native pituitary cells (PMID:18202135), and mouse knockouts lose cardiac AC stimulation (PMID:8693001). IBA node PTN001205212 covers beta-adrenergic receptors and is sound. Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:18202135 The present data suggest that beta(1)-AR in the anterior pituitary is positively coupled to adenylyl cyclase but is constitutively active in a pertussis toxin-sensitive manner. PMID:8693001 this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0071880 adenylate cyclase-activating adrenergic receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Core process: Gs/adenylyl cyclase-coupled adrenergic signalling. Reason: Rat beta1 stimulates adenylyl cyclase when expressed (PMID:1695899), is coupled to AC in native pituitary cells (PMID:18202135), and mouse knockouts lose cardiac AC stimulation (PMID:8693001). IBA node PTN001205212 covers beta-adrenergic receptors and is sound. Supporting Evidence: PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype PMID:18202135 The present data suggest that beta(1)-AR in the anterior pituitary is positively coupled to adenylyl cyclase but is constitutively active in a pertussis toxin-sensitive manner. PMID:8693001 this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice UniProtKB:P18090 G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway |
| GO:0086004 regulation of cardiac muscle cell contraction | IDA PMID:19525381 Adenoprotection of the heart involves phospholipase C-induce... | MODIFY | Summary: Beta1 stimulation increases cardiomyocyte shortening; positive regulation is the precise term. Reason: Isoproterenol increases rat cardiomyocyte sarcomere shortening (rat ventricular myocytes are beta1-dominated) and the contraction is blocked by the beta1 antagonist CGP 20712A (PMID:22216755). The direction is known, so the positive-regulation child applies. Proposed replacements: positive regulation of cardiac muscle cell contraction Supporting Evidence: PMID:19525381 the beta-adrenergic agonist isoproterenol increased sarcomere shortening by 177% PMID:22216755 the effect was inhibited by Ξ²(1)-AR antagonist, CGP 20712A, instead of Ξ²(2)-AR antagonist, ICI 118,551 |
| GO:0086004 regulation of cardiac muscle cell contraction | IMP PMID:22216755 Ξ²2-adrenoceptor transfection enhances contractile reserve of... | MODIFY | Summary: Beta1 stimulation increases cardiomyocyte shortening; positive regulation is the precise term. Reason: Isoproterenol increases rat cardiomyocyte sarcomere shortening (rat ventricular myocytes are beta1-dominated) and the contraction is blocked by the beta1 antagonist CGP 20712A (PMID:22216755). The direction is known, so the positive-regulation child applies. Proposed replacements: positive regulation of cardiac muscle cell contraction Supporting Evidence: PMID:19525381 the beta-adrenergic agonist isoproterenol increased sarcomere shortening by 177% PMID:22216755 the effect was inhibited by Ξ²(1)-AR antagonist, CGP 20712A, instead of Ξ²(2)-AR antagonist, ICI 118,551 |
| GO:0098685 Schaffer collateral - CA1 synapse | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1-AR acts at hippocampal CA1 synapses to promote ERK-dependent LTP (mouse); non-core. Reason: Mouse donor shows beta1 activation paired with 5 Hz stimulation induces ERK-dependent LTP in CA1 (PMID:10595521). Synaptic location is real but peripheral to the core cardiac/endocrine role. Supporting Evidence: PMID:10595521 LTP elicited by more prolonged 5 Hz stimulation when paired with beta1-adrenergic receptor activation |
| GO:0098794 postsynapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Postsynapse inferred from the IPSP annotation; independently plausible from PDZ scaffolding with PSD-95/MAGI-2. Reason: The inference chain is weak (the source IPSP study points to presynaptic beta1), but beta1 binds postsynaptic density scaffolds PSD-95 and MAGI-2 (PMID:11526121, PMID:16316992), so a postsynaptic pool is supported. Non-core. Supporting Evidence: PMID:11526121 The beta1AR carboxyl terminus binds with high affinity to the first PDZ domain of MAGI-2 PMID:16316992 The beta1AR carboxyl terminus was found to bind specifically to the first PDZ domain of MAGI-3, with the last four amino acids (E-S-K-V) of beta1AR being the key determinants of the interaction. |
| GO:0098992 neuronal dense core vesicle | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1-AR is carried on large dense-core vesicles in DRG neurons (mouse); non-core. Reason: LDCV proteomics and imaging place beta1 in SP-negative LDCVs (PMID:21321602), a delivery route to the surface, not the site of function. Supporting Evidence: PMID:21321602 whereas Ξ²1 AR, Wnt receptor frizzled 8 and dishevelled 1 were present in SP-negative LDCVs |
| GO:0099528 G protein-coupled neurotransmitter receptor activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: In neurons beta1-AR is the G protein-coupled receptor for the neurotransmitter norepinephrine. Reason: This synapse-context MF is not an ancestor of GO:0004940 but describes the same activity at synapses (mouse CA1 LTP, PMID:10595521). Kept as non-core; GO:0004940 is the core MF. Supporting Evidence: PMID:10595521 LTP elicited by more prolonged 5 Hz stimulation when paired with beta1-adrenergic receptor activation PMID:1695899 adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype |
| GO:0106071 positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway | IMP PMID:18202135 Beta1-adrenoceptors in rat anterior pituitary may be constit... | MODIFY | Summary: The cited study shows that beta1 itself is coupled to adenylyl cyclase (with constitutive activity), not that it regulates another pathway. Reason: Inverse agonism of CGP 20712A on basal cAMP shows beta1 is the receptor of the AC-activating pathway; the receptor is a participant, so GO:0071880 is the right term. Proposed replacements: adenylate cyclase-activating adrenergic receptor signaling pathway Supporting Evidence: PMID:18202135 The present data suggest that beta(1)-AR in the anterior pituitary is positively coupled to adenylyl cyclase but is constitutively active in a pertussis toxin-sensitive manner. |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta1-AR mediates most sympathetic stimulation of adaptive (cold- and diet-induced) thermogenesis; non-core. Reason: Beta1-KO mice are cold intolerant with reduced BAT thermal response (PMID:22728333); triple-KO data (PMID:12387862) agree but are less specific. Supporting Evidence: PMID:22728333 the Ξ²(1) signaling pathway mediates most of the SNS stimulation of adaptive thermogenesis PMID:22728333 developed hypothermia during cold exposure PMID:12387862 Hence, beta-adrenergic signalling is essential for the resistance to obesity and cold |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:12387862 Beta(1)/beta(2)/beta(3)-adrenoceptor knockout mice are obese... | KEEP AS NON CORE | Summary: Beta1-AR mediates most sympathetic stimulation of adaptive (cold- and diet-induced) thermogenesis; non-core. Reason: Beta1-KO mice are cold intolerant with reduced BAT thermal response (PMID:22728333); triple-KO data (PMID:12387862) agree but are less specific. Supporting Evidence: PMID:22728333 the Ξ²(1) signaling pathway mediates most of the SNS stimulation of adaptive thermogenesis PMID:22728333 developed hypothermia during cold exposure PMID:12387862 Hence, beta-adrenergic signalling is essential for the resistance to obesity and cold |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:22728333 Ξ²(1) Adrenergic receptor is key to cold- and diet-induced th... | KEEP AS NON CORE | Summary: Beta1-AR mediates most sympathetic stimulation of adaptive (cold- and diet-induced) thermogenesis; non-core. Reason: Beta1-KO mice are cold intolerant with reduced BAT thermal response (PMID:22728333); triple-KO data (PMID:12387862) agree but are less specific. Supporting Evidence: PMID:22728333 the Ξ²(1) signaling pathway mediates most of the SNS stimulation of adaptive thermogenesis PMID:22728333 developed hypothermia during cold exposure PMID:12387862 Hence, beta-adrenergic signalling is essential for the resistance to obesity and cold |
| GO:1900273 positive regulation of long-term synaptic potentiation | IDA PMID:21848869 Hidden prenatal malnutrition in the rat: role of Ξ²β-adrenoce... | KEEP AS NON CORE | Summary: Beta1 agonism rescues prefrontal LTP in prenatally malnourished rats; non-core. Reason: Dobutamine (beta1-selective) restored LTP (PMID:21848869); consistent with mouse CA1 data (PMID:10595521). Neuromodulatory output. Supporting Evidence: PMID:21848869 Administration of the selective Ξ²β agonist dobutamine prior to tetanization completely rescued the ability of the prefrontal cortex to develop and maintain long-term potentiation in the malnourished rats. PMID:10595521 LTP elicited by more prolonged 5 Hz stimulation when paired with beta1-adrenergic receptor activation |
| GO:1905665 positive regulation of calcium ion import across plasma membrane | IDA PMID:11408541 Enhanced cardiac L-type calcium current response to beta2-ad... | KEEP AS NON CORE | Summary: Beta1 signalling increases L-type Ca2+ influx via PKA in rat chromaffin cells and cardiomyocytes. Reason: Well supported for beta1 by PMID:12514203 and PMID:19133992. The cited IDA (PMID:11408541) abstract concerns beta2 and reports that a beta1 antagonist did not modify the zinterol effect; the curator may have used full-text data not visible here, so the row is kept (function is true for beta1) and flagged. Non-core downstream effector regulation. Supporting Evidence: PMID:12514203 suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs PMID:19133992 Both rolipram and cilostamide augmented the (-)-noradrenaline (1 micromol x L(-1)) evoked increase in I(Ca-L). PMID:11408541 These effects were not modified by the incubation of myocytes with CGP-20712A (3 x 10(-7) M), a beta1-AR antagonist |
| GO:1905665 positive regulation of calcium ion import across plasma membrane | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Beta1 signalling increases L-type Ca2+ influx via PKA in rat chromaffin cells and cardiomyocytes. Reason: Well supported for beta1 by PMID:12514203 and PMID:19133992. The cited IDA (PMID:11408541) abstract concerns beta2 and reports that a beta1 antagonist did not modify the zinterol effect; the curator may have used full-text data not visible here, so the row is kept (function is true for beta1) and flagged. Non-core downstream effector regulation. Supporting Evidence: PMID:12514203 suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs PMID:19133992 Both rolipram and cilostamide augmented the (-)-noradrenaline (1 micromol x L(-1)) evoked increase in I(Ca-L). PMID:11408541 These effects were not modified by the incubation of myocytes with CGP-20712A (3 x 10(-7) M), a beta1-AR antagonist |
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Download this section (compressed HTML)Q: Is the landiolol-induced, Rho-kinase-dependent tracheal contraction (PMID:18306009) mediated by Adrb1 at all, given the 700 microM concentration? If not, the Rho signal transduction and smooth-muscle-contraction rows should be removed.
Q: Should the human/mouse UniProt IMP annotations to GO:0045187 be re-keyed from PMID:25083013 (BHLHE41) to PMID:31473062 (ADRB1 short-sleep variant)?
Q: Does PMID:11408541 contain beta1-specific data on L-type Ca2+ current that justifies the rat IDA to GO:1905665, or was the row intended for Adrb2?
Experiment: Knock in a C-terminal V466A mutation in rat Adrb1 (abolishing PDZ binding) and compare isoproterenol-induced Ras-GTP, ERK1/2 activation, cAMP and hypertrophy in neonatal cardiomyocytes and in vivo.
Hypothesis: In rat cardiomyocytes, the PDZ ligand-dependent beta1-RAPGEF2 interaction routes cAMP to Ras/ERK activation and contributes to beta1-specific hypertrophy.
Type: genetic perturbation with signalling readouts
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