provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2026-02-08T20:24:18.942473'
end_time: '2026-02-08T20:32:21.044244'
duration_seconds: 482.1
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: ADM2
gene_symbol: ADM2
uniprot_accession: Q7Z4H4
protein_description: 'RecName: Full=Protein ADM2; AltName: Full=Intermedin {ECO:0000303|PubMed:14615490};
Contains: RecName: Full=Adrenomedullin-2 {ECO:0000303|PubMed:16359754}; Short=AM2;
AltName: Full=Intermedin-long; Short=IMDL; Contains: RecName: Full=Intermedin-short;
Short=IMDS; Flags: Precursor;'
gene_info: Name=ADM2 {ECO:0000312|HGNC:HGNC:28898}; Synonyms=AM2;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the adrenomedullin family. .
protein_domains: Adrenomedullin-reg_peptide. (IPR051665)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 45

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: Q7Z4H4
• Protein Description: RecName: Full=Protein ADM2; AltName: Full=Intermedin {ECO:0000303|PubMed:14615490}; Contains: RecName: Full=Adrenomedullin-2 {ECO:0000303|PubMed:16359754}; Short=AM2; AltName: Full=Intermedin-long; Short=IMDL; Contains: RecName: Full=Intermedin-short; Short=IMDS; Flags: Precursor;
• Gene Information: Name=ADM2 {ECO:0000312|HGNC:HGNC:28898}; Synonyms=AM2;
• Organism (full): Homo sapiens (Human).
• Protein Family: Belongs to the adrenomedullin family. .
• Key Domains: Adrenomedullin-reg_peptide. (IPR051665)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "ADM2" matches the protein description above
2. Verify the organism is correct: Homo sapiens (Human).
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ADM2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene ADM2 (gene ID: ADM2, UniProt: Q7Z4H4) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: Q7Z4H4
• Protein Description: RecName: Full=Protein ADM2; AltName: Full=Intermedin {ECO:0000303|PubMed:14615490}; Contains: RecName: Full=Adrenomedullin-2 {ECO:0000303|PubMed:16359754}; Short=AM2; AltName: Full=Intermedin-long; Short=IMDL; Contains: RecName: Full=Intermedin-short; Short=IMDS; Flags: Precursor;
• Gene Information: Name=ADM2 {ECO:0000312|HGNC:HGNC:28898}; Synonyms=AM2;
• Organism (full): Homo sapiens (Human).
• Protein Family: Belongs to the adrenomedullin family. .
• Key Domains: Adrenomedullin-reg_peptide. (IPR051665)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "ADM2" matches the protein description above
2. Verify the organism is correct: Homo sapiens (Human).
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ADM2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene ADM2 (gene ID: ADM2, UniProt: Q7Z4H4) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan
- Verify identity and resolve potential symbol ambiguity using human-focused, authoritative sources (UniProt description cross-checked against human literature). Collect and synthesize 2023–2024 developments on ADM2/CALCRL–RAMP signaling, structure, genetics, and metabolism. Summarize molecular function, processing, receptors, signaling, localization/expression, and precise physiological roles. Document translational/clinical implementations (biomarkers, therapeutic strategies) and pregnancy/placenta roles. Provide quantitative data where available, prioritize recent, peer‑reviewed sources, and include URLs and publication dates.

Verification of Target Identity and Nomenclature
- Target: Human ADM2 (adrenomedullin‑2), also known as intermedin (IMD), encoded on human chromosome 22q13.33; UniProt Q7Z4H4 corresponds to a 148‑aa prepro‑peptide processed to biologically active C‑terminal fragments. ADM2 belongs to the calcitonin/CGRP peptide family and functions as a secreted regulatory peptide. These features are consistent with the UniProt brief and with authoritative human literature; no conflicting non‑human gene symbol usage was used for this report. (https://doi.org/10.1111/bph.13814, Apr 2018; https://doi.org/10.1038/sj.bjp.0707494, Mar 2008; https://doi.org/10.1007/s11427-014-4701-7, Aug 2014) (zhang2018adrenomedullin2intermedina pages 1-3, bell2008intermedin(adrenomedullin‐2)a pages 1-2, ni2014intermedinadrenomedullin2anautocrineparacrine pages 1-2)

Key concepts and definitions
- Molecular identity and processing. ADM2/IMD is synthesized as prepro‑IMD (~148 aa) and proteolytically processed to multiple active C‑terminal peptides, notably IMD1–53, IMD1–47, and IMD8–47; fragments display distinct bioactivities across CLR/RAMP receptor subtypes. Dibasic cleavage sites have been mapped in mammals; IMD1–53 and IMD8–47 are established as physiologically relevant forms. (https://doi.org/10.1038/sj.bjp.0707494, Mar 2008; https://doi.org/10.1007/s11427-014-4701-7, Aug 2014; https://doi.org/10.1111/bph.13814, Apr 2018) (bell2008intermedin(adrenomedullin‐2)a pages 1-2, ni2014intermedinadrenomedullin2anautocrineparacrine pages 1-2, zhang2018adrenomedullin2intermedina pages 1-3)
- Receptors and selectivity. ADM2 signals via the class B1 GPCR calcitonin receptor‑like receptor (CALCRL/CLR) in complex with receptor activity‑modifying proteins (RAMPs): CLR+RAMP2 (AM1 receptor), CLR+RAMP3 (AM2 receptor), and CLR+RAMP1 (CGRP receptor). RAMP identity governs trafficking, ligand affinity/selectivity and signaling bias. Relative to CGRP and ADM, ADM2 shows distinct potency profiles across these complexes. (https://doi.org/10.1007/s11427-014-4701-7, Aug 2014; https://doi.org/10.1111/bph.13814, Apr 2018; https://doi.org/10.1038/sj.bjp.0707494, Mar 2008) (ni2014intermedinadrenomedullin2anautocrineparacrine pages 2-4, zhang2018adrenomedullin2intermedina pages 3-4, bell2008intermedin(adrenomedullin‐2)a pages 1-2)
- Downstream signaling. Canonical coupling is Gs→adenylyl cyclase→cAMP/PKA; additional pathways include Gq/PLCβ→Ca2+, ERK activation, and NO generation via L‑arginine transport and eNOS, linking to cGMP signaling and endothelial function. RAMP composition can bias G‑protein usage and downstream pathways. (https://doi.org/10.1007/s11427-014-4701-7, Aug 2014; https://doi.org/10.1111/bph.13814, Apr 2018) (ni2014intermedinadrenomedullin2anautocrineparacrine pages 2-4, zhang2018adrenomedullin2intermedina pages 3-4)
- Structural/biophysical family features. Members of the calcitonin/CGRP family share an N‑terminal disulfide‑bonded loop and helical core; receptor recognition predominantly involves the C‑terminal region in a two‑domain binding mode typical of class B GPCRs. These features rationalize ADM/ADM2 pharmacology at CLR/CTR–RAMP complexes. (https://doi.org/10.1002/psc.2953, Jul 2017) (schonauer2017adrenomedullin–new pages 2-2)

Recent developments and latest research (2023–2024 emphasis)
- RAMPs as allosteric modulators and determinants of bias. A 2024 review synthesizes data showing RAMPs alter GPCR phenotype, ligand preference, signaling bias, trafficking and recycling, extending beyond CLR/CTR to other class B1 GPCRs; these insights solidify that pharmacology of ADM2 is context‑dependent on RAMP isoform and expression in metabolic tissues. Human Protein Atlas‑based mapping (accessed 2024) supports tissue‑specific RAMP distributions relevant for ADM2 actions. (https://doi.org/10.1530/jme-24-0056, Sep 2024) (malcharek2024theroleof pages 31-35, malcharek2024theroleof pages 35-42, malcharek2024theroleof pages 21-26)
- Human CALCRL variants. A 2024 thesis characterizes a naturally occurring CALCRL variant (I446T; rs369317777) enriched in Polynesian populations: prior overexpression assays suggested minimal effects, but more physiological constructs and iPSC‑derived endothelial models revealed reduced AM‑induced cAMP efficacy; ADM2 was included among ligands tested. Clinically, carriers showed lower systolic blood pressure, but in diabetes had worse kidney outcomes, supporting physiologic relevance of variant‑dependent CLR signaling. (2024 thesis; institutional repository, includes primary data and literature synthesis) (reith2024characterisationofa pages 8-14, reith2024characterisationofa pages 23-27)
- Structural context. Recent syntheses referenced by 2024 works emphasize cryo‑EM/structural studies resolving CLR/RAMP complexes and G‑protein coupling that explain RAMP‑dependent receptor phenotype for CGRP/AM/AM2 receptors, strengthening mechanistic bases for ADM2 selectivity and bias. (2024 compilation citing Liang et al. 2018/2020) (reith2024characterisationofa pages 91-93)
- Metabolic relevance and RAMP expression. 2024 analysis compiles evidence that ADM2 supports adipose browning/beiging, improves insulin resistance and energy expenditure in rodent models, and that RAMP isoform balance (e.g., RAMP3 loss) modulates obesity phenotypes—together indicating therapeutic potential at specific CLR/RAMP complexes in metabolic disease. (https://doi.org/10.1530/jme-24-0056, Sep 2024) (malcharek2024theroleof pages 13-17)
- Overall interpretation. 2023–2024 literature refines rather than overturns ADM2 pharmacology: it underscores RAMP‑determined receptor context, highlights genetic variation affecting signaling, and extends relevance to metabolism, aligning with earlier proposals of receptor‑complex‑specific therapeutic strategies. (https://doi.org/10.1530/jme-24-0056, Sep 2024; 2024 thesis) (malcharek2024theroleof pages 31-35, malcharek2024theroleof pages 35-42, reith2024characterisationofa pages 23-27)

Current applications and real‑world implementations
- Biomarkers. Two clinically used assay paradigms target the ADM axis: MR‑proADM (stable mid‑regional pro‑fragment) and bio‑ADM (assay for biologically active ADM). Bio‑ADM is elevated in cardiogenic shock and acute decompensated heart failure (ADHF), correlates with clinical congestion, and predicts 60‑day HF re‑hospitalization when measured at baseline and day 7 in ED/ADHF cohorts. (https://doi.org/10.1002/ejhf.1366, Dec 2019) (voors2019adrenomedullininheart pages 3-4)
- Therapeutics modulating the ADM axis. Adrecizumab is a humanized, non‑neutralizing monoclonal antibody that binds the N‑terminus of ADM, increasing intravascular ADM and stabilizing endothelial barrier function while limiting interstitial vasodilatory effects; early clinical testing in systemic inflammation/LPS challenge showed symptom score reduction, and a sepsis program was initiated. HF translation has been proposed given bio‑ADM’s link to congestion, though clinical efficacy data in HF remain limited. (https://doi.org/10.3389/fimmu.2018.00292, Feb 2018; https://doi.org/10.1002/ejhf.1366, Dec 2019) (geven2018adrenomedullinandadrenomedullintargeted pages 1-2, voors2019adrenomedullininheart pages 6-7, voors2019adrenomedullininheart pages 6-6)
- Pregnancy/placental context. In human placenta, ADM2 is expressed in cytotrophoblasts, syncytiotrophoblasts and endothelial cells, promotes trophoblast invasion/migration, and stimulates NO; second‑trimester amniotic fluid ADM2 was lower in women who later developed early preeclampsia (n=17 vs 12 controls), and ADM2–CRLR proximity was reduced in preeclamptic villous tissue, indicating a pathophysiologic association with defective placentation. (https://doi.org/10.1095/biolreprod.108.074419, Oct 2009; https://doi.org/10.1210/jc.2016-1333, Sep 2016) (chauhan2009expressionofadrenomedullin pages 2-3, chauhan2016adrenomedullin2(adm2)intermedin(imd) pages 6-7, chauhan2016adrenomedullin2(adm2)intermedin(imd) pages 2-3)

Expert opinions and analysis from authoritative sources
- Cardiovascular/renal counter‑regulatory peptide. Early authoritative reviews defined ADM2/IMD as a potent vasodilator with cardiopulmonary and renal protective actions, distinct receptor selectivity across CLR/RAMP complexes, and low basal plasma levels consistent with autocrine/paracrine roles. (https://doi.org/10.1038/sj.bjp.0707494, Mar 2008) (bell2008intermedin(adrenomedullin‐2)a pages 1-2)
- Vascular homeostasis. A 2014 review framed ADM2 as an autocrine/paracrine regulator of vascular homeostasis—enhancing barrier function, pro‑angiogenesis and anti‑oxidative/ER‑stress responses—via CLR/RAMP signaling with cAMP/NO pathways. (https://doi.org/10.1007/s11427-014-4701-7, Aug 2014) (ni2014intermedinadrenomedullin2anautocrineparacrine pages 2-4, ni2014intermedinadrenomedullin2anautocrineparacrine pages 1-2)
- Translational framing in HF and sepsis. Clinical reviews emphasize bio‑ADM as a congestion biomarker and discuss the Adrecizumab concept to rebalance compartmental ADM; they also outline the need for definitive outcome trials. (https://doi.org/10.1002/ejhf.1366, Dec 2019; https://doi.org/10.3389/fimmu.2018.00292, Feb 2018) (voors2019adrenomedullininheart pages 6-7, voors2019adrenomedullininheart pages 6-6, voors2019adrenomedullininheart pages 3-4, geven2018adrenomedullinandadrenomedullintargeted pages 1-2)
- 2024 RAMP perspective. A 2024 mechanistic review argues for targeting specific GPCR/RAMP complexes to achieve desired metabolic and cardiovascular outcomes, citing evidence of RAMP‑dependent signaling bias and tissue‑specific RAMP expression that conditions ADM2 responses. (https://doi.org/10.1530/jme-24-0056, Sep 2024) (malcharek2024theroleof pages 31-35, malcharek2024theroleof pages 35-42, malcharek2024theroleof pages 21-26)

Relevant statistics and data
- Circulating levels. Plasma ADM2 is typically low (~100–200 pg/mL) but rises in pregnancy and under certain stressors such as hypoxia and ER stress, supporting both paracrine and endocrine actions. (https://doi.org/10.1111/bph.13814, Apr 2018) (zhang2018adrenomedullin2intermedina pages 1-3)
- Placental/preeclampsia association. In a second‑trimester cohort, amniotic fluid ADM2 levels were lower in women who later developed early preeclampsia (n=17) compared with controls (n=12), and placental ADM2–CRLR proximity was reduced in preeclampsia (PLA assay). (https://doi.org/10.1210/jc.2016-1333, Sep 2016) (chauhan2016adrenomedullin2(adm2)intermedin(imd) pages 6-7, chauhan2016adrenomedullin2(adm2)intermedin(imd) pages 2-3)
- Bio‑ADM prognostic performance. Bio‑ADM concentrations at presentation and day 7 in ADHF associate with clinical congestion and add predictive value for 60‑day re‑hospitalization beyond standard variables; bio‑ADM is elevated in cardiogenic shock with strong links to impaired hemodynamics and organ dysfunction. (https://doi.org/10.1002/ejhf.1366, Dec 2019) (voors2019adrenomedullininheart pages 3-4)
- Genetic variation. CALCRL I446T (rs369317777) associates with lower systolic blood pressure in healthy carriers and worse renal outcomes in diabetes; in iPSC‑EC models the variant reduces AM‑induced cAMP efficacy, highlighting functional impact of naturally occurring receptor variation. (2024 thesis) (reith2024characterisationofa pages 23-27)

Molecular function and pathway placement
- Primary role. ADM2 is a secreted signaling peptide of the calcitonin/CGRP superfamily. It activates CALCRL/CLR in complex with RAMP2 or RAMP3 (AM1/AM2 receptors) and can also engage CLR/RAMP1 (CGRP receptor) with lower potency; signaling is dominated by Gs/cAMP with context‑dependent recruitment of Ca2+, ERK and NO pathways. Mechanistically, ADM2 regulates vascular tone, endothelial barrier integrity, angiogenesis, and trophoblast invasion, linking to vascular homeostasis, cardiovascular protection and placentation. (https://doi.org/10.1007/s11427-014-4701-7, Aug 2014; https://doi.org/10.1038/sj.bjp.0707494, Mar 2008; https://doi.org/10.1111/bph.13814, Apr 2018) (ni2014intermedinadrenomedullin2anautocrineparacrine pages 2-4, bell2008intermedin(adrenomedullin‐2)a pages 1-2, zhang2018adrenomedullin2intermedina pages 3-4)
- Localization. ADM2 is processed in the secretory pathway and acts primarily in the extracellular space in autocrine/paracrine fashion; expression is documented in endothelial cells, vascular smooth muscle, placenta/trophoblast, kidney, and stressed myocardium/endothelium, with low basal plasma concentrations. (https://doi.org/10.1007/s11427-014-4701-7, Aug 2014; https://doi.org/10.1095/biolreprod.108.074419, Oct 2009; https://doi.org/10.1111/bph.13814, Apr 2018) (ni2014intermedinadrenomedullin2anautocrineparacrine pages 1-2, chauhan2009expressionofadrenomedullin pages 2-3, zhang2018adrenomedullin2intermedina pages 1-3)
- Developmental and disease links. CLR/RAMP pathway integrity is essential for vascular/lymphatic function; human CALCRL mutations and natural variants link to lymphatic dysplasia and altered hemodynamic traits, consistent with ADM/ADM2 family roles in vascular development and homeostasis. (2024 synthesis of prior studies) (reith2024characterisationofa pages 91-93)

Open questions and future directions (guided by recent literature)
- Precise in vivo abundance and receptor‑selective actions of specific ADM2 fragments (IMD1–53 vs IMD1–47 vs IMD8–47) in humans remain to be fully quantified with fragment‑selective assays. (https://doi.org/10.1111/bph.13814, Apr 2018) (zhang2018adrenomedullin2intermedina pages 7-8)
- Definitive clinical outcome trials testing ADM‑axis modulation (e.g., Adrecizumab) in sepsis and heart failure are needed to validate biomarker‑driven strategies and mechanistic hypotheses regarding compartmental redistribution. (https://doi.org/10.1002/ejhf.1366, Dec 2019; https://doi.org/10.3389/fimmu.2018.00292, Feb 2018) (voors2019adrenomedullininheart pages 6-7, voors2019adrenomedullininheart pages 6-6, geven2018adrenomedullinandadrenomedullintargeted pages 1-2)
- Context‑specific targeting of CLR/RAMP complexes (AM1 vs AM2 vs CGRP receptors) may enable tissue‑selective therapies in cardiometabolic disease; RAMP expression maps and human genetic variation should inform indication selection and safety. (https://doi.org/10.1530/jme-24-0056, Sep 2024; 2024 thesis) (malcharek2024theroleof pages 31-35, malcharek2024theroleof pages 35-42, reith2024characterisationofa pages 23-27)

Quick‑reference summary table
| Category | Key Points | Primary Sources (with year) |
|---|---|---|
| Identity & gene | Human ADM2 (Intermedin, IMD) is encoded by a gene at 22q13.33 and translated as a ~148 amino-acid prepro‑peptide (prepro‑IMD/Q7Z4H4). It is a member of the CGRP/ADM peptide family and processed to shorter secreted peptides. | [pqac-00000000] 2018, [pqac-00000003] 2008, [pqac-00000004] 2014 |
| Proteolytic processing | The prepropeptide is proteolytically processed to multiple C‑terminal bioactive fragments including IMD1–53, IMD1–47 and IMD8–47; distinct fragments show different receptor potencies and physiological activities. Proteolytic pattern and fragment-specific activity contribute to functional diversity. | [pqac-00000003] 2008, [pqac-00000001] 2014, [pqac-00000000] 2018 |
| Receptors | ADM2/IMD signals via CALCRL (CLR) when partnered with RAMPs: CLR+RAMP2 (AM1), CLR+RAMP3 (AM2) and CLR+RAMP1 (CGRP context); RAMP identity strongly alters ligand affinity and receptor phenotype. ADM2 displays distinct ligand selectivity across CLR/RAMP complexes versus ADM and CGRP. | [pqac-00000001] 2014, [pqac-00000002] 2018, [pqac-00000004] 2014 |
| Signaling | Canonical signaling is Gs‑coupled → AC → cAMP; additional pathways include Gq/PLC→Ca2+, ERK activation and NOS/NO/cGMP effects. RAMP composition can produce biased G‑protein coupling and alter downstream effector engagement. | [pqac-00000001] 2014, [pqac-00000002] 2018, [pqac-00000005] 2017 |
| Expression & localization | ADM2 is synthesized as a secreted peptide by endothelial cells, vascular smooth muscle, placenta/trophoblast, kidney and some cardiac tissues; plasma levels are low but inducible (e.g., pregnancy, hypoxia). Subcellularly it is processed through secretory pathway and acts in autocrine/paracrine and endocrine modes. | [pqac-00000004] 2014, [pqac-00000021] 2009, [pqac-00000000] 2018 |
| Physiological roles | ADM2 mediates vasodilation and regional blood‑flow modulation, protects endothelial barrier integrity, promotes angiogenesis and confers cardioprotective/anti‑oxidative effects; it also promotes trophoblast invasion and may contribute to placental function. Many actions are consistent with a vascular homeostasis/counter‑regulatory role. | [pqac-00000004] 2014, [pqac-00000003] 2008, [pqac-00000021] 2009, [pqac-00000018] 2016 |
| Recent (2023–2024) developments | Recent work emphasizes that RAMPs can act as allosteric modulators producing receptor‑ and ligand‑specific bias, identifies naturally occurring CALCRL variants that alter CLR signaling/physiology, and links ADM2/CLR–RAMP pathways to metabolic regulation and tissue‑specific RAMP expression. These findings refine ADM2 pharmacology and suggest context‑dependent signaling. | [pqac-00000006] 2024, [pqac-00000007] 2024, [pqac-00000009] 2024, [pqac-00000010] 2024 |
| Translational / clinical | Bio‑ADM and MR‑proADM assays are used as biomarkers of congestion and prognosis in heart failure and sepsis; Adrecizumab (N‑terminal ADM‑binding antibody) is a translational strategy to modulate intravascular vs interstitial ADM activity in sepsis/HF contexts. ADM2 shows pregnancy associations (reduced in preeclampsia) but clinical ADM2‑specific therapeutics are not yet established. | [pqac-00000015] 2019, [pqac-00000020] 2018, [pqac-00000018] 2016, [pqac-00000017] 2019 |

Table: A concise reference table summarizing ADM2 (Intermedin) identity, processing, receptors, signaling, expression, physiology, recent 2023–2024 developments, and translational/clinical notes with source IDs for quick citation.

References (with URLs and dates inline; bracketed IDs correspond to cited context)
- Zhang S‑Y et al. Br J Pharmacol. Apr 2018. https://doi.org/10.1111/bph.13814 (zhang2018adrenomedullin2intermedina pages 1-3, zhang2018adrenomedullin2intermedina pages 3-4, zhang2018adrenomedullin2intermedina pages 7-8)
- Ni XQ et al. Sci China Life Sci. Aug 2014. https://doi.org/10.1007/s11427-014-4701-7 (ni2014intermedinadrenomedullin2anautocrineparacrine pages 2-4, ni2014intermedinadrenomedullin2anautocrineparacrine pages 1-2)
- Bell D, McDermott B. Br J Pharmacol. Mar 2008. https://doi.org/10.1038/sj.bjp.0707494 (bell2008intermedin(adrenomedullin‐2)a pages 1-2)
- Schönauer R et al. J Pept Sci. Jul 2017. https://doi.org/10.1002/psc.2953 (schonauer2017adrenomedullin–new pages 2-2)
- Malcharek MA et al. J Mol Endocrinol. Sep 2024. https://doi.org/10.1530/jme-24-0056 (malcharek2024theroleof pages 31-35, malcharek2024theroleof pages 35-42, malcharek2024theroleof pages 13-17, malcharek2024theroleof pages 21-26)
- Reith EG. Thesis on CALCRL variant, 2024. (Repository URL not provided in excerpt) (reith2024characterisationofa pages 8-14, reith2024characterisationofa pages 91-93, reith2024characterisationofa pages 23-27)
- Geven C et al. Front Immunol. Feb 2018. https://doi.org/10.3389/fimmu.2018.00292 (geven2018adrenomedullinandadrenomedullintargeted pages 1-2)
- Voors AA et al. Eur J Heart Fail. Dec 2019. https://doi.org/10.1002/ejhf.1366 (voors2019adrenomedullininheart pages 6-7, voors2019adrenomedullininheart pages 6-6, voors2019adrenomedullininheart pages 3-4)
- Chauhan M et al. Biol Reprod. Oct 2009. https://doi.org/10.1095/biolreprod.108.074419 (chauhan2009expressionofadrenomedullin pages 2-3)
- Chauhan M et al. J Clin Endocrinol Metab. Sep 2016. https://doi.org/10.1210/jc.2016-1333 (chauhan2016adrenomedullin2(adm2)intermedin(imd) pages 6-7, chauhan2016adrenomedullin2(adm2)intermedin(imd) pages 2-3)

References

1. (zhang2018adrenomedullin2intermedina pages 1-3): Song‐Yang Zhang, Ming‐Jiang Xu, and Xian Wang. Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases. British Journal of Pharmacology, 175:1230-1240, Apr 2018. URL: https://doi.org/10.1111/bph.13814, doi:10.1111/bph.13814. This article has 63 citations and is from a highest quality peer-reviewed journal.

2. (bell2008intermedin(adrenomedullin‐2)a pages 1-2): David Bell and B. McDermott. Intermedin (adrenomedullin‐2): a novel counter‐regulatory peptide in the cardiovascular and renal systems. British Journal of Pharmacology, Mar 2008. URL: https://doi.org/10.1038/sj.bjp.0707494, doi:10.1038/sj.bjp.0707494. This article has 154 citations and is from a highest quality peer-reviewed journal.

3. (ni2014intermedinadrenomedullin2anautocrineparacrine pages 1-2): XianQiang Ni, JinSheng Zhang, ChaoShu Tang, and YongFen Qi. Intermedin/adrenomedullin2: an autocrine/paracrine factor in vascular homeostasis and disease. Science China Life Sciences, 57:781-789, Aug 2014. URL: https://doi.org/10.1007/s11427-014-4701-7, doi:10.1007/s11427-014-4701-7. This article has 44 citations.

4. (ni2014intermedinadrenomedullin2anautocrineparacrine pages 2-4): XianQiang Ni, JinSheng Zhang, ChaoShu Tang, and YongFen Qi. Intermedin/adrenomedullin2: an autocrine/paracrine factor in vascular homeostasis and disease. Science China Life Sciences, 57:781-789, Aug 2014. URL: https://doi.org/10.1007/s11427-014-4701-7, doi:10.1007/s11427-014-4701-7. This article has 44 citations.

5. (zhang2018adrenomedullin2intermedina pages 3-4): Song‐Yang Zhang, Ming‐Jiang Xu, and Xian Wang. Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases. British Journal of Pharmacology, 175:1230-1240, Apr 2018. URL: https://doi.org/10.1111/bph.13814, doi:10.1111/bph.13814. This article has 63 citations and is from a highest quality peer-reviewed journal.

6. (schonauer2017adrenomedullin–new pages 2-2): Ria Schönauer, Sylvia Els‐Heindl, and Annette G. Beck‐Sickinger. Adrenomedullin – new perspectives of a potent peptide hormone. Journal of Peptide Science, 23:472-485, Jul 2017. URL: https://doi.org/10.1002/psc.2953, doi:10.1002/psc.2953. This article has 92 citations and is from a peer-reviewed journal.

7. (malcharek2024theroleof pages 31-35): Milena A Malcharek, Abigail Pearce, Cheryl A Brighton, David C Hornigold, and Graham Ladds. The role of receptor activity-modifying proteins in obesity and diabetes mellitus. Journal of Molecular Endocrinology, Sep 2024. URL: https://doi.org/10.1530/jme-24-0056, doi:10.1530/jme-24-0056. This article has 2 citations and is from a peer-reviewed journal.

8. (malcharek2024theroleof pages 35-42): Milena A Malcharek, Abigail Pearce, Cheryl A Brighton, David C Hornigold, and Graham Ladds. The role of receptor activity-modifying proteins in obesity and diabetes mellitus. Journal of Molecular Endocrinology, Sep 2024. URL: https://doi.org/10.1530/jme-24-0056, doi:10.1530/jme-24-0056. This article has 2 citations and is from a peer-reviewed journal.

9. (malcharek2024theroleof pages 21-26): Milena A Malcharek, Abigail Pearce, Cheryl A Brighton, David C Hornigold, and Graham Ladds. The role of receptor activity-modifying proteins in obesity and diabetes mellitus. Journal of Molecular Endocrinology, Sep 2024. URL: https://doi.org/10.1530/jme-24-0056, doi:10.1530/jme-24-0056. This article has 2 citations and is from a peer-reviewed journal.

10. (reith2024characterisationofa pages 8-14): EG Reith. Characterisation of a naturally occurring calcitonin receptor-like receptor variant. Unknown journal, 2024.

11. (reith2024characterisationofa pages 23-27): EG Reith. Characterisation of a naturally occurring calcitonin receptor-like receptor variant. Unknown journal, 2024.

12. (reith2024characterisationofa pages 91-93): EG Reith. Characterisation of a naturally occurring calcitonin receptor-like receptor variant. Unknown journal, 2024.

13. (malcharek2024theroleof pages 13-17): Milena A Malcharek, Abigail Pearce, Cheryl A Brighton, David C Hornigold, and Graham Ladds. The role of receptor activity-modifying proteins in obesity and diabetes mellitus. Journal of Molecular Endocrinology, Sep 2024. URL: https://doi.org/10.1530/jme-24-0056, doi:10.1530/jme-24-0056. This article has 2 citations and is from a peer-reviewed journal.

14. (voors2019adrenomedullininheart pages 3-4): Adriaan A. Voors, Daan Kremer, Christopher Geven, Jozine M. ter Maaten, Joachim Struck, Andreas Bergmann, Peter Pickkers, Marco Metra, Alexandre Mebazaa, Hans‐Dirk Düngen, and Javed Butler. Adrenomedullin in heart failure: pathophysiology and therapeutic application. European Journal of Heart Failure, 21:163-171, Dec 2019. URL: https://doi.org/10.1002/ejhf.1366, doi:10.1002/ejhf.1366. This article has 255 citations and is from a highest quality peer-reviewed journal.

15. (geven2018adrenomedullinandadrenomedullintargeted pages 1-2): Christopher Geven, Matthijs Kox, and Peter Pickkers. Adrenomedullin and adrenomedullin-targeted therapy as treatment strategies relevant for sepsis. Frontiers in Immunology, Feb 2018. URL: https://doi.org/10.3389/fimmu.2018.00292, doi:10.3389/fimmu.2018.00292. This article has 156 citations and is from a peer-reviewed journal.

16. (voors2019adrenomedullininheart pages 6-7): Adriaan A. Voors, Daan Kremer, Christopher Geven, Jozine M. ter Maaten, Joachim Struck, Andreas Bergmann, Peter Pickkers, Marco Metra, Alexandre Mebazaa, Hans‐Dirk Düngen, and Javed Butler. Adrenomedullin in heart failure: pathophysiology and therapeutic application. European Journal of Heart Failure, 21:163-171, Dec 2019. URL: https://doi.org/10.1002/ejhf.1366, doi:10.1002/ejhf.1366. This article has 255 citations and is from a highest quality peer-reviewed journal.

17. (voors2019adrenomedullininheart pages 6-6): Adriaan A. Voors, Daan Kremer, Christopher Geven, Jozine M. ter Maaten, Joachim Struck, Andreas Bergmann, Peter Pickkers, Marco Metra, Alexandre Mebazaa, Hans‐Dirk Düngen, and Javed Butler. Adrenomedullin in heart failure: pathophysiology and therapeutic application. European Journal of Heart Failure, 21:163-171, Dec 2019. URL: https://doi.org/10.1002/ejhf.1366, doi:10.1002/ejhf.1366. This article has 255 citations and is from a highest quality peer-reviewed journal.

18. (chauhan2009expressionofadrenomedullin pages 2-3): Madhu Chauhan, Uma Yallampalli, Yuan-Lin Dong, Gary D.V. Hankins, and Chandrasekhar Yallampalli. Expression of adrenomedullin 2 (adm2)/intermedin (imd) in human placenta: role in trophoblast invasion and migration1. Biology of Reproduction, 81:777-783, Oct 2009. URL: https://doi.org/10.1095/biolreprod.108.074419, doi:10.1095/biolreprod.108.074419. This article has 54 citations and is from a peer-reviewed journal.

19. (chauhan2016adrenomedullin2(adm2)intermedin(imd) pages 6-7): Madhu Chauhan, Meena Balakrishnan, Alex Vidaeff, Uma Yallampalli, Fernando Lugo, Karin Fox, Michael Belfort, and Chandra Yallampalli. Adrenomedullin2 (adm2)/intermedin (imd): a potential role in the pathophysiology of preeclampsia. The Journal of clinical endocrinology and metabolism, 101 11:4478-4488, Sep 2016. URL: https://doi.org/10.1210/jc.2016-1333, doi:10.1210/jc.2016-1333. This article has 15 citations.

20. (chauhan2016adrenomedullin2(adm2)intermedin(imd) pages 2-3): Madhu Chauhan, Meena Balakrishnan, Alex Vidaeff, Uma Yallampalli, Fernando Lugo, Karin Fox, Michael Belfort, and Chandra Yallampalli. Adrenomedullin2 (adm2)/intermedin (imd): a potential role in the pathophysiology of preeclampsia. The Journal of clinical endocrinology and metabolism, 101 11:4478-4488, Sep 2016. URL: https://doi.org/10.1210/jc.2016-1333, doi:10.1210/jc.2016-1333. This article has 15 citations.

21. (zhang2018adrenomedullin2intermedina pages 7-8): Song‐Yang Zhang, Ming‐Jiang Xu, and Xian Wang. Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases. British Journal of Pharmacology, 175:1230-1240, Apr 2018. URL: https://doi.org/10.1111/bph.13814, doi:10.1111/bph.13814. This article has 63 citations and is from a highest quality peer-reviewed journal.

Citations

1. reith2024characterisationofa pages 91-93
2. malcharek2024theroleof pages 13-17
3. voors2019adrenomedullininheart pages 3-4
4. reith2024characterisationofa pages 23-27
5. geven2018adrenomedullinandadrenomedullintargeted pages 1-2
6. chauhan2009expressionofadrenomedullin pages 2-3
7. malcharek2024theroleof pages 31-35
8. malcharek2024theroleof pages 35-42
9. malcharek2024theroleof pages 21-26
10. reith2024characterisationofa pages 8-14
11. voors2019adrenomedullininheart pages 6-7
12. voors2019adrenomedullininheart pages 6-6
13. pqac-00000000
14. pqac-00000003
15. pqac-00000004
16. pqac-00000001
17. pqac-00000002
18. pqac-00000005
19. pqac-00000021
20. pqac-00000018
21. pqac-00000006
22. pqac-00000007
23. pqac-00000009
24. pqac-00000010
25. pqac-00000015
26. pqac-00000020
27. pqac-00000017
28. https://doi.org/10.1111/bph.13814,
29. https://doi.org/10.1038/sj.bjp.0707494,
30. https://doi.org/10.1007/s11427-014-4701-7,
31. https://doi.org/10.1002/psc.2953,
32. https://doi.org/10.1530/jme-24-0056,
33. https://doi.org/10.1002/ejhf.1366,
34. https://doi.org/10.3389/fimmu.2018.00292,
35. https://doi.org/10.1095/biolreprod.108.074419,
36. https://doi.org/10.1210/jc.2016-1333,
37. https://doi.org/10.1111/bph.13814
38. https://doi.org/10.1007/s11427-014-4701-7
39. https://doi.org/10.1038/sj.bjp.0707494
40. https://doi.org/10.1002/psc.2953
41. https://doi.org/10.1530/jme-24-0056
42. https://doi.org/10.3389/fimmu.2018.00292
43. https://doi.org/10.1002/ejhf.1366
44. https://doi.org/10.1095/biolreprod.108.074419
45. https://doi.org/10.1210/jc.2016-1333