id: PW:0000794 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000794 title: epinephrine signaling pathway via adrenergic receptor beta description: Norepinephrine and epinephrine, whose synthesis and release are prompted by various but distinct stresses, act as neurotransmitters and hormones that signal via various adrenergic receptors, G-protein coupled receptors (GPCR) that couple to distinct G alpha subunits of heterotrimeric G proteins. The beta receptors, for which epinephrine appears to be a favorite agonist, couple to the Gs alpha subunit leading to activation of adenylyl cyclases, cAMP production and subsequent triggering of PKA signaling pathway. Of the three beta receptors, beta1 and beta2 are the better understood systems.The highest levels of beta1 are found in the heart and brain; beta2 is expressed in the heart, lung and other tissues. Beta2, due to its role in smooth muscle relaxation, has been the target for the development of short- and long-acting agonists used in the treatment of asthma. Both receptors are important for the stimulation of cardiac performance. Acute activation of the receptors following ventricular dysfunction, while initially beneficial, can lead to heart failure if it becomes chronic. Upon agonist binding, conformational changes lead to binding of the receptor to the GDP-bound G protein complex. Activated receptors act as GEFs to catalyze the release of GDP from the G alpha subunit followed by formation of a stable receptor-G protein complex. GTP binding to the alpha subunit triggers conformational re-arrangements leading to the dissociation of the GTP-bound G alpha from both the beta/gamma and receptor complexes and association with downstream effectors. For Gs alpha, the effectors are members of the adenylyl cyclase family that catalyze the conversion of ATP to cAMP. G alpha has intrinsic but slow GTPase activity; members of the RGS family act as GAPs to promote GTP hydrolysis, termination of the G-protein signal, and re-formation of the GDP-bound and inactive heterotrimer now ready for another possible cycle of activation. PKA signaling exerts a plethora of effects; among its targets in cardiac myocytes are proteins involved in excitation-contraction coupling. PKA phosphorylates the activated, ligand-bound beta1 and 2 receptors, also targets for phosphorylation by members of the GRK family. Subsequent interaction with beta-arrestin sterically precludes the coupling between the receptor and the G protein, an event referred to as receptor desensitization. Receptor desensitization is a hallmark of heart failure but its exact role in the condition is still to be determined. Beta-blockers, which compete with catecholamine binding to counteract excessive signaling and by the same token allow the system to 're-sensitize', are the main therapeutics used for treatment. Beta-arrestin is also involved in receptor internalization to clathrin-coated pits followed by clathrin-mediated endocytosis and receptor degradation (downregulation) or recycling, as needed. In addition, beta-arrestins also act as scaffolds to trigger G protein independent signaling pathways downstream of beta adrenergic and other GPCR receptors, primarily MAPK cascades. Of note is that in addition to common targets, the two receptors interact with distinct sets of proteins (not shown). diagram_image: https://rgd.mcw.edu/pathway/PW0000794/epinephrine%20signaling%20pathway%20via%20adrenergic%20receptor%20beta/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000794/epinephrine%20signaling%20pathway%20via%20adrenergic%20receptor%20beta/epinephrine%20signaling%20pathway%20via%20adrenergic%20receptor%20beta.gpp diagram_pathway_links: - id: PW:0000227 label: G protein mediated signaling pathway via Galphas family - id: PW:0000543 label: protein kinase A (PKA) signaling pathway - id: PW:0000803 label: epinephrine biosynthetic pathway diagram_gene_links: - id: RGD:2059 label: Adrb1 - id: RGD:2060 label: Adrb2 - id: RGD:2062 label: Adrbk1 - id: RGD:2156 label: Arrb1 - id: RGD:2157 label: Arrb2 - id: RGD:2716 label: Gnas - id: RGD:61985 label: Grk5 - id: RGD:1309778 label: Snx13 diagram_chemicals: - id: PUBCHEM.COMPOUND:6076 label: cAMP - id: PUBCHEM.COMPOUND:5816 label: epinephrine diagram_edges: - source: Adrb1 relation: associated_with target: Arrb1 - source: Adrb1 relation: associated_with target: Arrb2 - source: Adrb1 relation: associated_with target: Gnas - source: Adrb1 relation: associated_with target: epinephrine - source: Adrb2 relation: associated_with target: Arrb1 - source: Adrb2 relation: associated_with target: Arrb2 - source: Adrb2 relation: associated_with target: Gnas - source: Adrb2 relation: associated_with target: epinephrine - source: Adrbk1 relation: negatively_affects target: Adrb1 - source: Adrbk1 relation: negatively_affects target: Adrb2 - source: Arrb1 relation: positively_affects target: beta-arrestin mediated signaling - source: Arrb2 relation: positively_affects target: beta-arrestin mediated signaling - source: Grk5 relation: negatively_affects target: Adrb1 - source: Grk5 relation: negatively_affects target: Adrb2 - source: Snx13 relation: negatively_affects target: Gnas - source: epinephrine prompting stresses relation: positively_affects target: epinephrine - source: receptor - G protein uncoupling relation: negatively_affects target: G protein mediated signaling pathway via Galphas family diagram_labels: - beta-arrestin mediated signaling - cAMP --+> protein kinase A (PKA) signaling pathway - epinephrine prompting stresses - epinephrine release - G protein mediated signaling pathway via Galphas family --+> cAMP - receptor - G protein uncoupling - receptor internalization references: - id: RGD:4140388 citation: Xie GX and Palmer PP, J Mol Biol. 2007 Feb 16;366(2):349-65. 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