ADM2 (Adrenomedullin-2/Intermedin) encodes a secreted peptide hormone of the calcitonin/CGRP superfamily. The 148 amino acid prepro-protein is proteolytically processed to generate bioactive C-terminal peptides including IMD1-53, IMD1-47, and IMD8-47. ADM2 functions as a ligand for CALCRL/RAMP receptor complexes (AM1, AM2, and CGRP receptors), where RAMP identity determines receptor affinity and signaling bias. Canonical signaling is via Gs-coupled adenylyl cyclase/cAMP pathway, with additional engagement of Gq/Ca2+, ERK, and NOS/NO pathways. ADM2 acts as a potent vasodilator regulating systemic blood pressure, promotes angiogenesis, protects endothelial barrier integrity, and has roles in cardiovascular and renal homeostasis. It functions primarily in autocrine/paracrine mode with low basal plasma levels.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005179 hormone activity | IBA GO_REF:0000033 | ACCEPT | Summary: ADM2/Intermedin is a well-established peptide hormone of the calcitonin/CGRP family that signals through CALCRL/RAMP receptor complexes. The IBA annotation is phylogenetically sound and consistent with experimental data showing ADM2 activates cAMP-dependent pathways through these receptors [PMID:14615490, PMID:32296767]. Reason: Core function of ADM2 as a hormone is strongly supported by primary literature. ADM2 is synthesized as a prepropeptide and processed to secreted bioactive peptides that act as ligands for GPCR complexes, fulfilling the definition of hormone activity. Supporting Evidence: PMID:14615490 Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. PMID:32296767 In this study, we report the cryo-EM structure of the AM1R in complex with AM and Gs at a global resolution of 3.0 Å, and structures of the AM2R in complex with either AM or intermedin/adrenomedullin 2 (AM2) and Gs at 2.4 and 2.3 Å, respectively |
| GO:0005615 extracellular space | IBA GO_REF:0000033 | ACCEPT | Summary: ADM2 is a secreted peptide hormone that functions in the extracellular space to activate CALCRL/RAMP receptors. This is consistent with its signal peptide, secretory pathway processing, and autocrine/paracrine mode of action [PMID:14615490]. Reason: The extracellular space localization is correct for a secreted hormone that acts on cell surface receptors. UniProt confirms secreted localization. Supporting Evidence: PMID:14615490 Intermedin increased cAMP production in SK-N-MC and L6 cells expressing endogenous CGRP receptors |
| GO:0035809 regulation of urine volume | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ADM2/Intermedin has documented roles in renal function and diuresis, consistent with the broader adrenomedullin family. The deep research notes ADM2 has cardiopulmonary and renal protective actions [file:human/ADM2/ADM2-deep-research-falcon.md]. Reason: While ADM2 does affect renal function including urine volume, this represents a downstream physiological consequence of its vasodilatory and blood pressure regulatory effects rather than a core molecular function. The primary role is as a vasoactive hormone signaling through CALCRL/RAMP. Supporting Evidence: file:human/ADM2/ADM2-deep-research-falcon.md ADM2/IMD as a potent vasodilator with cardiopulmonary and renal protective actions |
| GO:1990410 adrenomedullin receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: ADM2 is a bona fide ligand for the adrenomedullin receptors (CALCRL+RAMP2/3). The IBA annotation is phylogenetically supported and consistent with structural and biochemical data showing ADM2 binding and activation of these receptors [PMID:14615490, PMID:32296767]. Reason: Core function of ADM2 is to act as a ligand in the adrenomedullin receptor signaling pathway. This is directly supported by cryo-EM structures of ADM2 in complex with AM2R. Supporting Evidence: PMID:32296767 In this study, we report the cryo-EM structure of the AM1R in complex with AM and Gs at a global resolution of 3.0 Å, and structures of the AM2R in complex with either AM or intermedin/adrenomedullin 2 (AM2) and Gs at 2.4 and 2.3 Å, respectively PMID:14615490 treatment of 293T cells expressing recombinant calcitonin receptor-like receptor (CRLR) and one of the three receptor activity-modifying proteins (RAMPs) showed that a CRLR/RAMP receptor complex is required for intermedin signaling |
| GO:0003073 regulation of systemic arterial blood pressure | IBA GO_REF:0000033 | ACCEPT | Summary: ADM2/Intermedin is a potent vasodilator that reduces systemic arterial blood pressure. In vivo studies demonstrated blood pressure reduction in both normal and spontaneously hypertensive rats [PMID:14615490]. Reason: Blood pressure regulation is a core physiological function of ADM2, directly linked to its vasodilatory activity through CALCRL/RAMP signaling. Supporting Evidence: PMID:14615490 In vivo studies demonstrated that intermedin treatment led to blood pressure reduction in both normal and spontaneously hypertensive rats via interactions with the CRLR/RAMP receptor complexes |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: ADM2 signals through CALCRL/RAMP receptor complexes coupled to Gs, leading to adenylyl cyclase activation and cAMP production. This is the canonical downstream signaling pathway [PMID:14615490]. Reason: This accurately describes the primary signaling mechanism of ADM2. As a ligand for CALCRL/RAMP GPCRs, it triggers Gs-coupled adenylyl cyclase activation. Supporting Evidence: PMID:14615490 Intermedin increased cAMP production in SK-N-MC and L6 cells expressing endogenous CGRP receptors |
| GO:0010460 positive regulation of heart rate | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ADM2/Intermedin has documented cardiovascular effects including effects on heart rate. The literature indicates ADM2 is important for homeostasis in diverse tissues including cardiovascular [PMID:14615490]. Reason: While ADM2 does have cardiovascular effects that may include heart rate modulation, this represents a downstream physiological consequence rather than a core molecular function. The primary functions are hormone activity, receptor signaling, and blood pressure regulation. Supporting Evidence: PMID:14615490 Calcitonin, calcitonin gene-related peptide (CGRP), adrenomedullin (ADM), and amylin belong to a unique group of peptide hormones important for homeostasis in diverse tissues |
| GO:0005179 hormone activity | IEA GO_REF:0000043 | ACCEPT | Summary: This IEA annotation from UniProt keyword mapping correctly identifies ADM2 as having hormone activity. It is redundant with the IBA and IDA annotations for the same term. Reason: Correct annotation, though redundant with IBA/IDA evidence for the same term. The UniProt keyword mapping is appropriate. Supporting Evidence: PMID:14615490 Intermedin is a calcitonin/calcitonin gene-related peptide family peptide |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: This IEA annotation from UniProt subcellular location mapping correctly places ADM2 in the extracellular region. Consistent with its secreted nature. Reason: Correct annotation. ADM2 is a secreted protein and functions in the extracellular region. This is a broader parent term of extracellular space (GO:0005615). Supporting Evidence: PMID:14615490 Intermedin increased cAMP production in SK-N-MC and L6 cells expressing endogenous CGRP receptors |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: This IEA annotation from Ensembl Compara orthology transfer is consistent with the IBA annotation for the same term. Redundant but correct. Reason: Correct annotation, redundant with IBA evidence. The orthology-based transfer is appropriate for this conserved signaling function. Supporting Evidence: PMID:14615490 Intermedin increased cAMP production in SK-N-MC and L6 cells |
| GO:0007631 feeding behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The original PMID:14615490 reports that intermedin treatment in mice led to suppression of food intake, supporting a role in feeding behavior regulation. This IEA is transferred from rat ortholog evidence. Reason: While ADM2 does affect feeding behavior (suppresses food intake and gastric emptying per PMID:14615490), this is not a core molecular function but rather a downstream physiological effect of its neuroendocrine activity. The primary function is as a vasoactive hormone. Supporting Evidence: PMID:14615490 in vivo treatment in mice with intermedin led to suppression of gastric emptying activity and food intake |
| GO:0045776 negative regulation of blood pressure | IEA GO_REF:0000107 | ACCEPT | Summary: ADM2 is a potent vasodilator that reduces blood pressure. This is well supported by PMID:14615490 showing blood pressure reduction in normal and hypertensive rats. Reason: Correct and important annotation. ADM2 is a vasodilator that negatively regulates blood pressure. This is a core physiological function consistent with its role as a vasoactive hormone. Supporting Evidence: PMID:14615490 In vivo studies demonstrated that intermedin treatment led to blood pressure reduction in both normal and spontaneously hypertensive rats |
| GO:0005179 hormone activity | IDA PMID:32296767 Structure and Dynamics of Adrenomedullin Receptors AM(1) and... | ACCEPT | Summary: PMID:32296767 provides structural evidence of ADM2 (intermedin) in complex with AM2 receptor and Gs protein at 2.3 angstrom resolution, demonstrating it functions as a hormone ligand for this receptor complex. Reason: Strong structural evidence supporting hormone activity. The cryo-EM structure directly shows ADM2 peptide bound to and activating the receptor complex. Supporting Evidence: PMID:32296767 In this study, we report the cryo-EM structure of the AM1R in complex with AM and Gs at a global resolution of 3.0 Å, and structures of the AM2R in complex with either AM or intermedin/adrenomedullin 2 (AM2) and Gs at 2.4 and 2.3 Å, respectively |
| GO:0005615 extracellular space | IDA PMID:14615490 Intermedin is a calcitonin/calcitonin gene-related peptide f... | ACCEPT | Summary: PMID:14615490 demonstrates that intermedin acts on cell surface receptors to activate intracellular signaling (cAMP production), indicating it functions in the extracellular space. Reason: Appropriate localization for a secreted peptide hormone that activates cell surface receptors. Supporting Evidence: PMID:14615490 Intermedin increased cAMP production in SK-N-MC and L6 cells expressing endogenous CGRP receptors and competed with labeled CGRP for binding to its receptors in these cells |
| GO:1990410 adrenomedullin receptor signaling pathway | IDA PMID:32296767 Structure and Dynamics of Adrenomedullin Receptors AM(1) and... | ACCEPT | Summary: PMID:32296767 provides direct structural evidence of ADM2 bound to the AM2 receptor (CALCRL+RAMP3) in complex with Gs protein, demonstrating its involvement in adrenomedullin receptor signaling. Reason: High-resolution structural evidence directly demonstrates ADM2 engagement with the adrenomedullin receptor signaling pathway. Supporting Evidence: PMID:32296767 In this study, we report the cryo-EM structure of the AM1R in complex with AM and Gs at a global resolution of 3.0 Å, and structures of the AM2R in complex with either AM or intermedin/adrenomedullin 2 (AM2) and Gs at 2.4 and 2.3 Å, respectively |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-379044 | ACCEPT | Summary: Reactome pathway annotation placing ADM2 in the extracellular region as part of the Gs-activating GPCR signaling complex. Consistent with its role as a secreted hormone ligand. Reason: Correct localization. ADM2 is a secreted ligand that functions in the extracellular region where it binds to cell surface receptors. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-420214 | ACCEPT | Summary: Reactome annotation specifically documenting that intermedin (ADM2) binds to the adrenomedullin receptor in the extracellular region. Reason: Directly relevant Reactome annotation. The reaction specifically describes ADM2/intermedin binding to adrenomedullin receptors. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-744886 | ACCEPT | Summary: Reactome annotation for ligand:GPCR:Gs complex dissociation, placing ADM2 in the extracellular region. Redundant with other extracellular region annotations. Reason: Correct localization, though redundant with multiple other annotations for the same term. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-744887 | ACCEPT | Summary: Reactome annotation for liganded Gs-activating GPCRs binding inactive heterotrimeric Gs. Places ADM2 as extracellular ligand. Reason: Correct localization, though redundant with multiple other annotations for the same term. |
| GO:0001525 angiogenesis | IDA PMID:20596610 Involvement of vascular endothelial growth factor signaling ... | KEEP AS NON CORE | Summary: PMID:20596610 demonstrates that intermedin (IMD) exerts a pro-angiogenic effect on human vascular endothelial cells cultured on Matrigel, mediated through CLR/RAMP1 and CLR/RAMP2 receptors. Reason: While ADM2 does promote angiogenesis, this is a downstream biological process resulting from its signaling activity rather than a core molecular function. The core function is hormone activity through receptor signaling. The more specific term GO:0045766 (positive regulation of angiogenesis) better captures the regulatory nature of this activity. Supporting Evidence: PMID:20596610 IMD exerted a significant in vitro angiogenic action, specifically triggered by the binding of the peptide to CLR/RAMP complexes |
| GO:0006468 protein phosphorylation | IDA PMID:20596610 Involvement of vascular endothelial growth factor signaling ... | REMOVE | Summary: OVER-ANNOTATION: ADM2 is a secreted peptide hormone that acts as a LIGAND for GPCR receptors (CALCRL/RAMP complexes). It has NO kinase activity. PMID:20596610 shows ADM2 treatment leads to increased VEGF receptor-2 phosphorylation, but ADM2 does not catalyze phosphorylation itself - it triggers signaling that leads to kinase activation. Reason: This annotation incorrectly implies ADM2 has a direct role in protein phosphorylation. ADM2 is a peptide hormone ligand, not a kinase. The phosphorylation observed in PMID:20596610 (VEGFR-2 phosphorylation) is a downstream consequence of ADM2 signaling, not a direct function of the protein. The GO term "protein phosphorylation" is meant for proteins that catalyze phosphorylation reactions. Supporting Evidence: PMID:20596610 Western blot analysis, however, showed a significant increase of VEGF receptor-2 phosphorylation as early as 5 min following IMD administration |
| GO:0010628 positive regulation of gene expression | IDA PMID:20596610 Involvement of vascular endothelial growth factor signaling ... | KEEP AS NON CORE | Summary: PMID:20596610 shows that intermedin treatment leads to increased VEGF mRNA expression 18h after administration, indicating positive regulation of gene expression. Reason: While ADM2 does positively regulate gene expression (e.g., VEGF), this is a downstream consequence of its receptor signaling activity rather than a core molecular function. The term is also quite broad; a more specific annotation regarding VEGF expression would be more informative. Supporting Evidence: PMID:20596610 a significant increase of vascular endothelial growth factor (VEGF) mRNA expression 18 h following IMD administration |
| GO:0044877 protein-containing complex binding | IDA PMID:20596610 Involvement of vascular endothelial growth factor signaling ... | MODIFY | Summary: This annotation likely refers to ADM2 binding to the CALCRL/RAMP receptor complex. While technically accurate, "protein-containing complex binding" is a very general term that does not adequately describe the specific hormone-receptor interaction. Reason: This term is too vague and uninformative. ADM2 specifically binds to CALCRL/RAMP receptor complexes as a hormone ligand. The "hormone activity" annotation better captures this function. If a binding term is needed, a more specific term like G protein-coupled receptor binding would be more appropriate, though the hormone activity annotation already implies receptor binding. Proposed replacements: G protein-coupled receptor binding Supporting Evidence: PMID:20596610 IMD exerted a significant in vitro angiogenic action, specifically triggered by the binding of the peptide to CLR/RAMP complexes |
| GO:0045766 positive regulation of angiogenesis | IDA PMID:19592612 Intermedin is a new angiogenic growth factor. | KEEP AS NON CORE | Summary: PMID:19592612 provides strong evidence that intermedin promotes angiogenesis through multiple mechanisms including increased blood perfusion, capillary and arteriole density in ischemic hindlimb, endothelial cell migration and tube formation, mediated via ERK, Akt/NOS/NO, and VEGF/VEGFR-2 pathways. Reason: ADM2 does positively regulate angiogenesis, which is a significant biological function. However, this represents a downstream effect of its hormone signaling activity rather than the core molecular function. The primary functions are hormone activity and receptor signaling. Supporting Evidence: PMID:19592612 IMD gene delivery also increased capillary and arteriole density in ischemic hindlimb PMID:19592612 In cultured endothelial cells, IMD induced cell migration and tube formation |
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