Endothelin receptor signaling pathway module

The endothelin receptor signaling pathway (GO:0086100) and its canonical phospholipase C-activating branch (GO:0160135) are initiated when the secreted 21-amino-acid bicyclic peptide hormones endothelin-1 (EDN1, PANTHER:PTHR13874:SF10), endothelin-2 (EDN2, PANTHER:PTHR13874:SF9), and endothelin-3 (EDN3, PANTHER:PTHR13874:SF11) bind and activate their cognate seven-transmembrane G protein-coupled receptors EDNRA (ETA, PANTHER:PTHR46099:SF2; selective for EDN1 and EDN2 over EDN3) and EDNRB (ETB, PANTHER:PTHR46099:SF3; equipotent for EDN1, EDN2, and EDN3) at the plasma membrane of vascular smooth-muscle cells, endothelial cells, neural crest derivatives, and renal/cardiac tissues. Agonist-bound EDNRA and EDNRB couple primarily to heterotrimeric Gq/11 proteins (exemplified by GNAQ, PANTHER:PTHR10218:SF329) to stimulate phospholipase C-beta (PLCB1, PANTHER:PTHR10336:SF12), hydrolyzing phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) to mobilize intracellular Ca2+ and regulate vascular tone, systemic arterial blood pressure, and enteric/melanocytic neural crest development.

MODULE:endothelin_receptor_signalingDRAFTSignaling Pathwaymodules/endothelin_receptor_signaling.yaml
endothelin receptor signaling pathwayGO:0086100 phospholipase C-activating endothelin receptor signaling pathwayGO:0160135
GO:0086100
endothelin receptor signaling pathway
The module is grounded in the GO biological process term for the endothelin receptor signaling pathway (GO:0086100) and its specific phospholipase C-activating branch (GO:0160135).
GO:0160135
phospholipase C-activating endothelin receptor signaling pathway
Models the canonical Gq/11-phospholipase C-activating endothelin receptor signaling cascade (GO:0160135) triggered by EDN1, EDN2, and EDN3 across EDNRA and EDNRB.
Reactome:R-HSA-388560
EDNRA,EDNRB bind EDNs
Establishes that all three endothelin isopeptides (EDN1, EDN2, EDN3) bind and activate the endothelin GPCRs EDNRA and EDNRB.
There are 3 isoforms derived from the genes EDN1, EDN2 and EDN3 (Inoue et al. 1989).<br><br>EDNs bind to two receptors (Elshourbagy et al. 1993), EDNRA (Adachi et al. 1991) and EDNRB (Nakamuta et al. 1991).
PMID:2649896
The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes.
Demonstrates that the three human genes EDN1, EDN2, and EDN3 encode distinct 21-residue vasoactive endothelin peptide hormones.
Moreover, each of the human genes predicted a putative 21-residue peptide, similar to but distinct from each other: (i) the "classical" endothelin (ET-1), (ii) [Trp6,Leu7]endothelin (ET-2), and (iii) [Thr2,Phe4,Thr5,Tyr6, Lys7,Tyr14]endothelin (ET-3). Synthetic ET-1, ET-2, and ET-3 were prepared according to the deduced amino acid sequences, and the biological activities were assayed by contraction of isolated porcine coronary artery strips and by intravenous injection to anesthetized rats. All these synthetic peptides produced strong vasoconstrictor and pressor responses.
PMID:1917960
Effects of endothelins on signal transduction and proliferation in human melanocytes.
Establishes that mature ET-1 (EDN1), ET-2 (EDN2), and ET-3 (EDN3) directly stimulate phospholipase C to generate IP3 and mobilize intracellular Ca2+ (GO:0160135).
Upon incubation with cultured cells, the mass contents of inositol 1,4,5-trisphosphate and intracellular calcium level were substantially increased by 10 nM ET-1, ET-2, and ET-3, but not by big-ET with maximal response at 80-130-s postincubation.
PMID:1713452
Cloning and functional expression of human cDNA for the ETB endothelin receptor.
Demonstrates that human EDNRB binds EDN1 and EDN3 with equal potency to trigger intracellular Ca2+ mobilization.
COS cells transiently transfected with the cloned cDNA expressed specific, high-affinity binding sites for endothelin isopeptides and responded to the peptides with a transient increase of [Ca2+]i; endothelin-1 and endothelin-3 exhibited approximately equal potencies both in displacing 125I-labeled endothelin-1 binding and in eliciting [Ca2+]i transients.
PANTHER:PTN000356323
PAINT node PTN000356323 for the endothelin family (PTHR13874)
Local PAINT IBD root node in PTHR13874 with propagated terms C:GO:0005576, F:GO:0005179, F:GO:0031708, P:GO:0003100, P:GO:0006874, P:GO:0014826, P:GO:0045987; PAINT date 20260529.

Curated signaling-pathway module for the endothelin receptor signaling pathway (GO:0086100) and its phospholipase C-activating branch (GO:0160135) built with PANTHER FAMILY/subfamily selectors across the three endogenous endothelin peptide hormones EDN1 (PANTHER:PTHR13874:SF10), EDN2 (PANTHER:PTHR13874:SF9), and EDN3 (PANTHER:PTHR13874:SF11), their cognate GPCRs EDNRA (PANTHER:PTHR46099:SF2) and EDNRB (PANTHER:PTHR46099:SF3), and downstream Gq/11 alpha (GNAQ, PANTHER:PTHR10218:SF329) and phospholipase C-beta (PLCB1, PANTHER:PTHR10336:SF12) effectors.

3Nodes
2Parts
0Variant Sets
0Variants
7Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:endothelin_receptor_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

3 gene-function check(s) reflected in core functions · 0 conflict(s) · 7 evidence or coverage gap(s) (14 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
edn1_endothelin_1_ligand EDN1
UniProtKB:P05305
Family Representative 		hormone activity
GO:0005179 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
edn2_endothelin_2_ligand EDN2
UniProtKB:P20800
Family Representative 		hormone activity
GO:0005179 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
edn3_endothelin_3_ligand EDN3
UniProtKB:P14138
Family Representative 		hormone activity
GO:0005179 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ednra_receptor EDNRA
UniProtKB:P25101
Family Representative 		endothelin receptor activity
GO:0004962 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
ednrb_receptor EDNRB
UniProtKB:P24530
Family Representative 		endothelin receptor activity
GO:0004962 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
gnaq_gq_alpha GNAQ
UniProtKB:P50148
Family Representative 		G protein activity
GO:0003925 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
plcb1_phospholipase_c_beta PLCB1
UniProtKB:Q9NQ66
Family Representative 		phosphatidylinositol phospholipase C activity
GO:0004435 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
edn1_endothelin_1_ligand Endothelin-1 subfamily
PANTHER:PTHR13874:SF10
Family 		hormone activity
GO:0005179 		Family Supported
Family review supports GO:0005179 FAMILY_WIDE. All members of PANTHER:PTHR13874 (EDN1 in SF10, EDN2 in SF9, and EDN3 in SF11) function as secreted peptide hormones enabling GO:0005179.
edn2_endothelin_2_ligand Endothelin-2 subfamily
PANTHER:PTHR13874:SF9
Family 		hormone activity
GO:0005179 		Family Supported
Family review supports GO:0005179 FAMILY_WIDE. All members of PANTHER:PTHR13874 (EDN1 in SF10, EDN2 in SF9, and EDN3 in SF11) function as secreted peptide hormones enabling GO:0005179.
edn3_endothelin_3_ligand Endothelin-3 subfamily
PANTHER:PTHR13874:SF11
Family 		hormone activity
GO:0005179 		Family Supported
Family review supports GO:0005179 FAMILY_WIDE. All members of PANTHER:PTHR13874 (EDN1 in SF10, EDN2 in SF9, and EDN3 in SF11) function as secreted peptide hormones enabling GO:0005179.
ednra_receptor Endothelin-1 receptor subfamily
PANTHER:PTHR46099:SF2
Family 		endothelin receptor activity
GO:0004962 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR46099:SF2.
ednrb_receptor Endothelin receptor type B subfamily
PANTHER:PTHR46099:SF3
Family 		endothelin receptor activity
GO:0004962 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR46099:SF3.
gnaq_gq_alpha Guanine nucleotide-binding protein G(q) subunit alpha subfamily
PANTHER:PTHR10218:SF329
Family 		G protein activity
GO:0003925 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10218:SF329.
plcb1_phospholipase_c_beta 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 subfamily
PANTHER:PTHR10336:SF12
Family 		phosphatidylinositol phospholipase C activity
GO:0004435 		Family Supported
Family review supports GO:0004435 FAMILY_WIDE. Every reviewed member (fungal PLC1/plc1, PLCG1, PLCG2) accepts it. fgfr_signaling selects SF173 (PLCG1) and myo_inositol_and_inositol_phosphate_biosynthesis selects SF36 (fungal PLC).

Gene-review completeness (3/7 grounded genes reviewed)

2 complete review(s) · 0 with deep research · 4 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
EDN1 P05305 ✓ ✓ ✗
EDN3 P14138 ✓ ✓ ✗
GNAQ P50148 ✓ 111/121 ✗
EDN2 P20800 ✗ — —
EDNRB P24530 ✗ — —
EDNRA P25101 ✗ — —
PLCB1 Q9NQ66 ✗ — —

Details

Context
EuteleostomiNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829
Endothelin receptor signaling pathwaySignaling Pathwayendothelin_receptor_signaling
endothelin receptor signaling pathwayGO:0086100 phospholipase C-activating endothelin receptor signaling pathwayGO:0160135
Context
EuteleostomiNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829

Connections

Binding of mature EDN1, EDN2, or EDN3 to EDNRA or EDNRB stabilizes the active receptor conformation that catalyzes GDP-to-GTP exchange on GNAQ and activates PLCB1.
Part 1: endothelin peptide hormone ligand-receptor engagement
EDN1, EDN2, and EDN3 engagement of endothelin receptors EDNRA and EDNRBRegulatory Stependothelin_receptor_engagement

Secreted mature 21-residue bicyclic endothelin peptides EDN1, EDN2, and EDN3 (generated from big endothelins by endothelin-converting enzymes ECE1/ECE2) bind the orthosteric pockets of the seven-transmembrane endothelin receptors EDNRA (ETA; selective for EDN1 and EDN2) and EDNRB (ETB; nonselective across EDN1, EDN2, and EDN3) at the plasma membrane.

Annotons

EDN1 endothelin-1 peptide hormone ligand
edn1_endothelin_1_ligand
Participant: Family: Endothelin-1 subfamily
Family:
Endothelin-1 subfamilyPANTHER:PTHR13874:SF10
Representative Members: EDN1UniProtKB:P05305

Function

hormone activityGO:0005179

Processes

endothelin receptor signaling pathwayGO:0086100 phospholipase C-activating endothelin receptor signaling pathwayGO:0160135

Locations

extracellular regionGO:0005576

Predominant vascular endothelial endothelin peptide hormone that binds and activates both EDNRA and EDNRB with subnanomolar affinity to initiate phospholipase C-activating endothelin receptor signaling.

Reactome:R-HSA-388560
EDNRA,EDNRB bind EDNs
Establishes EDN1 as a high-affinity endogenous agonist of both EDNRA and EDNRB.
There are 3 isoforms derived from the genes EDN1, EDN2 and EDN3 (Inoue et al. 1989).<br><br>EDNs bind to two receptors (Elshourbagy et al. 1993), EDNRA (Adachi et al. 1991) and EDNRB (Nakamuta et al. 1991).
PMID:1917960
Effects of endothelins on signal transduction and proliferation in human melanocytes.
Demonstrates that mature EDN1 activates phospholipase C and IP3/Ca2+ signaling (GO:0160135).
Upon incubation with cultured cells, the mass contents of inositol 1,4,5-trisphosphate and intracellular calcium level were substantially increased by 10 nM ET-1, ET-2, and ET-3, but not by big-ET
EDN2 endothelin-2 peptide hormone ligand
edn2_endothelin_2_ligand
Participant: Family: Endothelin-2 subfamily
Family:
Endothelin-2 subfamilyPANTHER:PTHR13874:SF9
Representative Members: EDN2UniProtKB:P20800

Function

hormone activityGO:0005179

Processes

endothelin receptor signaling pathwayGO:0086100 phospholipase C-activating endothelin receptor signaling pathwayGO:0160135

Locations

extracellular regionGO:0005576

Endogenous endothelin isopeptide ([Trp6,Leu7]endothelin) that binds and activates both EDNRA and EDNRB with high affinity to initiate phospholipase C-activating endothelin receptor signaling.

Reactome:R-HSA-388560
EDNRA,EDNRB bind EDNs
Establishes EDN2 as a high-affinity endogenous agonist of both EDNRA and EDNRB.
There are 3 isoforms derived from the genes EDN1, EDN2 and EDN3 (Inoue et al. 1989).<br><br>EDNs bind to two receptors (Elshourbagy et al. 1993), EDNRA (Adachi et al. 1991) and EDNRB (Nakamuta et al. 1991).
PMID:1917960
Effects of endothelins on signal transduction and proliferation in human melanocytes.
Demonstrates that mature EDN2 activates phospholipase C and IP3/Ca2+ signaling (GO:0160135).
Upon incubation with cultured cells, the mass contents of inositol 1,4,5-trisphosphate and intracellular calcium level were substantially increased by 10 nM ET-1, ET-2, and ET-3, but not by big-ET
EDN3 endothelin-3 peptide hormone ligand
edn3_endothelin_3_ligand
Participant: Family: Endothelin-3 subfamily
Family:
Endothelin-3 subfamilyPANTHER:PTHR13874:SF11
Representative Members: EDN3UniProtKB:P14138

Function

hormone activityGO:0005179

Processes

endothelin receptor signaling pathwayGO:0086100 phospholipase C-activating endothelin receptor signaling pathwayGO:0160135

Locations

extracellular regionGO:0005576

Endogenous endothelin isopeptide that binds and activates EDNRB with high affinity (and EDNRA at higher concentrations) to initiate phospholipase C-activating endothelin receptor signaling essential for enteric and melanocytic neural crest development and vascular regulation.

PMID:1713452
Cloning and functional expression of human cDNA for the ETB endothelin receptor.
Establishes EDN3 as a full, equipotent endogenous agonist of EDNRB eliciting intracellular Ca2+ transients.
endothelin-1 and endothelin-3 exhibited approximately equal potencies both in displacing 125I-labeled endothelin-1 binding and in eliciting [Ca2+]i transients.
PMID:1917960
Effects of endothelins on signal transduction and proliferation in human melanocytes.
Demonstrates that mature EDN3 directly stimulates phospholipase C and IP3/Ca2+ mobilization (GO:0160135).
Upon incubation with cultured cells, the mass contents of inositol 1,4,5-trisphosphate and intracellular calcium level were substantially increased by 10 nM ET-1, ET-2, and ET-3, but not by big-ET
EDNRA endothelin-1 receptor (ETA)
ednra_receptor
Participant: Family: Endothelin-1 receptor subfamily
Family:
Endothelin-1 receptor subfamilyPANTHER:PTHR46099:SF2
Representative Members: EDNRAUniProtKB:P25101

Function

endothelin receptor activityGO:0004962

Processes

endothelin receptor signaling pathwayGO:0086100 phospholipase C-activating endothelin receptor signaling pathwayGO:0160135

Locations

plasma membraneGO:0005886

Seven-transmembrane G protein-coupled endothelin receptor type A (ETA) that binds EDN1 and EDN2 with high affinity and activates heterotrimeric Gq/11-phospholipase C signaling.

Reactome:R-HSA-388560
EDNRA,EDNRB bind EDNs
Establishes EDNRA as a principal mammalian endothelin receptor.
EDNs bind to two receptors (Elshourbagy et al. 1993), EDNRA (Adachi et al. 1991) and EDNRB (Nakamuta et al. 1991).
EDNRB endothelin receptor type B (ETB)
ednrb_receptor
Participant: Family: Endothelin receptor type B subfamily
Family:
Endothelin receptor type B subfamilyPANTHER:PTHR46099:SF3
Representative Members: EDNRBUniProtKB:P24530

Function

endothelin receptor activityGO:0004962

Processes

endothelin receptor signaling pathwayGO:0086100 phospholipase C-activating endothelin receptor signaling pathwayGO:0160135

Locations

plasma membraneGO:0005886

Seven-transmembrane G protein-coupled endothelin receptor type B (ETB) that binds EDN1, EDN2, and EDN3 with equal affinity and activates heterotrimeric Gq/11-phospholipase C signaling.

PMID:1713452
Cloning and functional expression of human cDNA for the ETB endothelin receptor.
Establishes EDNRB as a nonselective endothelin receptor coupled to Ca2+ mobilization.
COS cells transiently transfected with the cloned cDNA expressed specific, high-affinity binding sites for endothelin isopeptides and responded to the peptides with a transient increase of [Ca2+]i
Part 2: Gq/11 and phospholipase C-beta effector activation
Gq/11 and phospholipase C-beta effector activation downstream of EDNRA/EDNRBRegulatory Stependothelin_gq_plc_coupling

Agonist-activated EDNRA and EDNRB catalyze GDP-to-GTP exchange on heterotrimeric Gq/11 alpha subunits (exemplified by GNAQ), which directly stimulate plasma-membrane phospholipase C-beta (exemplified by PLCB1) to hydrolyze PIP2 into IP3 and DAG and mobilize intracellular Ca2+.

Annotons

GNAQ Gq alpha subunit
gnaq_gq_alpha
Participant: Family: Guanine nucleotide-binding protein G(q) subunit alpha subfamily
Family:
Guanine nucleotide-binding protein G(q) subunit alpha subfamilyPANTHER:PTHR10218:SF329
Representative Members: GNAQUniProtKB:P50148

Function

G protein activityGO:0003925

Processes

endothelin receptor signaling pathwayGO:0086100 phospholipase C-activating endothelin receptor signaling pathwayGO:0160135

Locations

plasma membraneGO:0005886

Heterotrimeric Gq alpha subunit activated by ligand-bound EDNRA and EDNRB to stimulate phospholipase C-beta.

Reactome:R-HSA-416476
G alpha (q) signalling events
Establishes that activated Gq/11 alpha subunits signal by stimulating phospholipase C-beta.
The classic signalling route for G alpha (q) is activation of phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation.
PLCB1 phospholipase C-beta-1 effector
plcb1_phospholipase_c_beta
Participant: Family: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 subfamily
Family:
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 subfamilyPANTHER:PTHR10336:SF12
Representative Members: PLCB1UniProtKB:Q9NQ66

Function

phosphatidylinositol phospholipase C activityGO:0004435

Processes

endothelin receptor signaling pathwayGO:0086100 phospholipase C-activating endothelin receptor signaling pathwayGO:0160135

Locations

plasma membraneGO:0005886

Phospholipase C-beta effector activated by GTP-bound GNAQ downstream of EDNRA and EDNRB to generate IP3 and DAG.

PMID:1917960
Effects of endothelins on signal transduction and proliferation in human melanocytes.
Demonstrates phospholipase C activation in endothelin receptor signaling.
Upon incubation with cultured cells, the mass contents of inositol 1,4,5-trisphosphate and intracellular calcium level were substantially increased by 10 nM ET-1, ET-2, and ET-3, but not by big-ET