G protein-coupled opioid receptor signaling pathway module

The G protein-coupled opioid receptor signaling pathway (GO:0038003) and its canonical adenylate cyclase-inhibiting branch (GO:0031635) are initiated when endogenous opioid and opioid-like neuropeptide precursors — proenkephalin-A (PENK, PANTHER:PTHR11438:SF3; cleaved into Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Phe, and Met-enkephalin-Arg-Gly-Leu), proenkephalin-B / prodynorphin (PDYN, PANTHER:PTHR11438:SF4; cleaved into dynorphin A, dynorphin B, alpha-/beta-neoendorphin, and Leu-enkephalin), and prepronociceptin (PNOC, PANTHER:PTHR11438:SF2; cleaved into nociceptin / orphanin FQ), together with pro-opiomelanocortin-derived beta-endorphin — are secreted from neuronal dense-core vesicles and bind the seven-transmembrane opioid receptor family GPCRs OPRM1 (mu-type opioid receptor, PANTHER:PTHR24229:SF7), OPRD1 (delta-type opioid receptor, PANTHER:PTHR24229:SF2), OPRK1 (kappa-type opioid receptor, PANTHER:PTHR24229:SF1), and OPRL1 (nociceptin/NOP receptor, PANTHER:PTHR24229:SF11) at the plasma membrane and synaptic membrane. Agonist-bound opioid receptors couple to pertussis-toxin-sensitive inhibitory heterotrimeric Gi/o proteins (exemplified by GNAI1, PANTHER:PTHR10218:SF359), inhibiting adenylate cyclase (exemplified by ADCY5, PANTHER:PTHR45627:SF7) to lower intracellular cAMP while released Gbeta-gamma dimers activate GIRK potassium channels and inhibit voltage-gated Ca2+ channels to suppress presynaptic neurotransmitter release and nociceptive transmission.

MODULE:opioid_receptor_signalingDRAFTSignaling Pathwaymodules/opioid_receptor_signaling.yaml
G protein-coupled opioid receptor signaling pathwayGO:0038003 adenylate cyclase-inhibiting opioid receptor signaling pathwayGO:0031635
GO:0038003
G protein-coupled opioid receptor signaling pathway
The module is grounded in the GO biological process term for the G protein-coupled opioid receptor signaling pathway (GO:0038003) and its canonical adenylate cyclase-inhibiting branch (GO:0031635).
GO:0031635
adenylate cyclase-inhibiting opioid receptor signaling pathway
Models the canonical Gi/o-coupled adenylate cyclase-inhibiting opioid receptor signaling cascade (GO:0031635) triggered by endogenous opioid peptides (PENK, PDYN, PNOC) across OPRM1, OPRD1, OPRK1, and OPRL1.
Reactome:R-HSA-111885
Opioid Signalling
Establishes that endogenous opioid peptides (enkephalins, endorphins, dynorphins) signal through the four classes of G protein-coupled opioid receptors (OPRM1/MOR, OPRD1/DOR, OPRK1/KOR, and OPRL1/NOP).
Opioid action is mediated by the receptors for endogenous opioids; peptides such as the enkephalins, the endorphins or the dynorphins. Opioids possess powerful analgesic and sedative effects, and are widely used as pain-killers. Their main side-effect is the rapid establishment of a strong addiction. Opioids receptors are G-protein coupled receptors (GPCR). There are four classes of receptors: mu (MOR), kappa (KOR) and delta (DOR), and the nociceptin receptor (NOP).
Reactome:R-HSA-418594
G alpha (i) signalling events
Establishes that activated Gi/o alpha subunits inhibit adenylate cyclase and decrease intracellular cAMP and cAMP-dependent protein kinase activity.
The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). Decreased production of cAMP from ATP results in decreased activity of cAMP-dependent protein kinases.
PMID:7057924
Primary structure of the human Met- and Leu-enkephalin precursor and its mRNA.
Demonstrates that human PENK encodes a polyprotein precursor yielding six Met-enkephalin and one Leu-enkephalin opioid peptides.
The corresponding amino acid sequence shows that the precursor is 267 amino acids long and contains six interspersed Met-enkephalin sequences and one Leu-enkephalin sequence. Five of the seven enkephalins are flanked on both sides by pairs of basic amino acid residues.
PMID:9047294
NMR and structural model of dynorphin A (1-17) bound to dodecylphosphocholine micelles.
Establishes PDYN-derived dynorphin A(1-17) as the high-affinity endogenous agonist of the kappa-opioid receptor (OPRK1).
Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand.
PANTHER:PTN000153716
PAINT node PTN000153716 for the proenkephalin/prodynorphin/pronociceptin family (PTHR11438)
Local PAINT IBD root node in PTHR11438 with propagated terms C:GO:0043025, F:GO:0001515, F:GO:0031628, P:GO:0007218, P:GO:0019233; PAINT date 20260828.

Curated signaling-pathway module for the G protein-coupled opioid receptor signaling pathway (GO:0038003) and its adenylate cyclase-inhibiting branch (GO:0031635) built with PANTHER FAMILY/subfamily selectors across the endogenous proenkephalin-family opioid peptide ligands PENK (PANTHER:PTHR11438:SF3), PDYN (PANTHER:PTHR11438:SF4), and PNOC (PANTHER:PTHR11438:SF2), their cognate GPCRs OPRM1 (PANTHER:PTHR24229:SF7), OPRD1 (PANTHER:PTHR24229:SF2), OPRK1 (PANTHER:PTHR24229:SF1), and OPRL1 (PANTHER:PTHR24229:SF11), and downstream Gi/o alpha (GNAI1, PANTHER:PTHR10218:SF359) and adenylate cyclase (ADCY5, PANTHER:PTHR45627:SF7) effectors.

3Nodes
2Parts
0Variant Sets
0Variants
9Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:opioid_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

4 gene-function check(s) reflected in core functions · 0 conflict(s) · 11 evidence or coverage gap(s) (18 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
penk_proenkephalin_ligand PENK
UniProtKB:P01210
Family Representative 		opioid peptide activity
GO:0001515 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pdyn_prodynorphin_ligand PDYN
UniProtKB:P01213
Family Representative 		opioid peptide activity
GO:0001515 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pnoc_prepronociceptin_ligand PNOC
UniProtKB:Q13519
Family Representative 		opioid peptide activity
GO:0001515 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
oprm1_mu_opioid_receptor OPRM1
UniProtKB:P35372
Family Representative 		G protein-coupled opioid receptor activity
GO:0004985 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
oprd1_delta_opioid_receptor OPRD1
UniProtKB:P41143
Family Representative 		G protein-coupled opioid receptor activity
GO:0004985 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
oprk1_kappa_opioid_receptor OPRK1
UniProtKB:P41145
Family Representative 		G protein-coupled opioid receptor activity
GO:0004985 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
oprl1_nociceptin_receptor OPRL1
UniProtKB:P41146
Family Representative 		G protein-coupled opioid receptor activity
GO:0004985 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
gnai1_gi_alpha GNAI1
UniProtKB:P63096
Family Representative 		G protein activity
GO:0003925 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
adcy5_adenylate_cyclase ADCY5
UniProtKB:O95622
Family Representative 		adenylate cyclase activity
GO:0004016 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
penk_proenkephalin_ligand Proenkephalin-A subfamily
PANTHER:PTHR11438:SF3
Family 		opioid peptide activity
GO:0001515 		Family Supported
Family review supports GO:0001515 FAMILY_WIDE. All members of PANTHER:PTHR11438 (PENK in SF3, PDYN in SF4, and PNOC in SF2) function as endogenous opioid peptide ligands enabling GO:0001515.
pdyn_prodynorphin_ligand Proenkephalin-B (prodynorphin) subfamily
PANTHER:PTHR11438:SF4
Family 		opioid peptide activity
GO:0001515 		Family Supported
Family review supports GO:0001515 FAMILY_WIDE. All members of PANTHER:PTHR11438 (PENK in SF3, PDYN in SF4, and PNOC in SF2) function as endogenous opioid peptide ligands enabling GO:0001515.
pnoc_prepronociceptin_ligand Prepronociceptin subfamily
PANTHER:PTHR11438:SF2
Family 		opioid peptide activity
GO:0001515 		Family Supported
Family review supports GO:0001515 FAMILY_WIDE. All members of PANTHER:PTHR11438 (PENK in SF3, PDYN in SF4, and PNOC in SF2) function as endogenous opioid peptide ligands enabling GO:0001515.
oprm1_mu_opioid_receptor Mu-type opioid receptor subfamily
PANTHER:PTHR24229:SF7
Family 		G protein-coupled opioid receptor activity
GO:0004985 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24229:SF7.
oprd1_delta_opioid_receptor Delta-type opioid receptor subfamily
PANTHER:PTHR24229:SF2
Family 		G protein-coupled opioid receptor activity
GO:0004985 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24229:SF2.
oprk1_kappa_opioid_receptor Kappa-type opioid receptor subfamily
PANTHER:PTHR24229:SF1
Family 		G protein-coupled opioid receptor activity
GO:0004985 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24229:SF1.
oprl1_nociceptin_receptor Nociceptin receptor subfamily
PANTHER:PTHR24229:SF11
Family 		G protein-coupled opioid receptor activity
GO:0004985 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24229:SF11.
gnai1_gi_alpha Guanine nucleotide-binding protein G(i) subunit alpha-1 subfamily
PANTHER:PTHR10218:SF359
Family 		G protein activity
GO:0003925 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10218:SF359.
adcy5_adenylate_cyclase Adenylate cyclase type 5 subfamily
PANTHER:PTHR45627:SF7
Family 		adenylate cyclase activity
GO:0004016 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR45627:SF7.

Gene-review completeness (4/9 grounded genes reviewed)

2 complete review(s) · 0 with deep research · 5 missing review · 4 reviewed but lacking deep research

Gene Review Complete Deep research
GNAI1 P63096 ✓ 140/146 ✗
ADCY5 O95622 ✗ — —
OPRM1 P35372 ✓ 94/97 ✗
OPRD1 P41143 ✗ — —
OPRK1 P41145 ✗ — —
OPRL1 P41146 ✗ — —
PDYN P01213 ✓ ✓ ✗
PENK P01210 ✓ ✓ ✗
PNOC Q13519 ✗ — —

Details

Context
EuteleostomiNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829
G protein-coupled opioid receptor signaling pathwaySignaling Pathwayopioid_receptor_signaling
G protein-coupled opioid receptor signaling pathwayGO:0038003 adenylate cyclase-inhibiting opioid receptor signaling pathwayGO:0031635
Context
EuteleostomiNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829

Connections

Binding of PENK-, PDYN-, or PNOC-derived opioid peptides to OPRM1, OPRD1, OPRK1, or OPRL1 stabilizes the active receptor conformation that catalyzes GDP-to-GTP exchange on GNAI1 and inhibits ADCY5.
Part 1: endogenous opioid peptide ligand-receptor engagement
PENK-, PDYN-, and PNOC-derived opioid peptide engagement of OPRM1, OPRD1, OPRK1, and OPRL1Regulatory Stepopioid_receptor_engagement

Secreted mature opioid peptides cleaved from proenkephalin-A (PENK: Met- and Leu-enkephalins), prodynorphin (PDYN: dynorphins A/B and neoendorphins), and prepronociceptin (PNOC: nociceptin/orphanin FQ) bind the orthosteric pockets of their cognate seven-transmembrane opioid receptors OPRD1 (delta), OPRM1 (mu), OPRK1 (kappa), and OPRL1 (nociceptin/NOP) at the plasma membrane and synaptic membrane via their N-terminal Tyr1/Phe1-Gly2-Gly3-Phe4 message sequence.

Annotons

PENK proenkephalin-A opioid peptide ligand
penk_proenkephalin_ligand
Participant: Family: Proenkephalin-A subfamily
Family:
Proenkephalin-A subfamilyPANTHER:PTHR11438:SF3
Representative Members: PENKUniProtKB:P01210

Function

opioid peptide activityGO:0001515

Processes

G protein-coupled opioid receptor signaling pathwayGO:0038003 adenylate cyclase-inhibiting opioid receptor signaling pathwayGO:0031635

Locations

extracellular regionGO:0005576

Endogenous opioid polyprotein precursor processed into Met-enkephalin and Leu-enkephalin pentapeptides (and C-terminally extended heptapeptide/octapeptide agonists) that preferentially bind and activate delta (OPRD1) and mu (OPRM1) opioid receptors to initiate Gi/o-coupled adenylate cyclase-inhibiting opioid receptor signaling.

PMID:7057924
Primary structure of the human Met- and Leu-enkephalin precursor and its mRNA.
Establishes human PENK as the precursor of endogenous Met- and Leu-enkephalin opioid receptor agonists.
The corresponding amino acid sequence shows that the precursor is 267 amino acids long and contains six interspersed Met-enkephalin sequences and one Leu-enkephalin sequence.
Reactome:R-HSA-418594
G alpha (i) signalling events
Demonstrates that PENK-derived opioid peptides signal through Gi/o-coupled opioid receptors to inhibit adenylate cyclase.
The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002).
PDYN prodynorphin (proenkephalin-B) opioid peptide ligand
pdyn_prodynorphin_ligand
Participant: Family: Proenkephalin-B (prodynorphin) subfamily
Family:
Proenkephalin-B (prodynorphin) subfamilyPANTHER:PTHR11438:SF4
Representative Members: PDYNUniProtKB:P01213

Function

opioid peptide activityGO:0001515

Processes

G protein-coupled opioid receptor signaling pathwayGO:0038003 adenylate cyclase-inhibiting opioid receptor signaling pathwayGO:0031635

Locations

extracellular regionGO:0005576

Endogenous opioid polyprotein precursor processed into dynorphin A, dynorphin B, and alpha-/beta-neoendorphin peptides that preferentially bind and activate the kappa-opioid receptor (OPRK1; and with lower selectivity OPRM1 and OPRD1) to initiate Gi/o-coupled adenylate cyclase-inhibiting opioid receptor signaling.

PMID:9047294
NMR and structural model of dynorphin A (1-17) bound to dodecylphosphocholine micelles.
Establishes PDYN-derived dynorphin A as the endogenous high-affinity agonist of OPRK1.
Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand.
Reactome:R-HSA-418594
G alpha (i) signalling events
Demonstrates that PDYN-derived dynorphin peptides signal through Gi/o-coupled OPRK1 to inhibit adenylate cyclase.
The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002).
PNOC prepronociceptin (nociceptin/orphanin FQ) ligand
pnoc_prepronociceptin_ligand
Participant: Family: Prepronociceptin subfamily
Family:
Prepronociceptin subfamilyPANTHER:PTHR11438:SF2
Representative Members: PNOCUniProtKB:Q13519

Function

opioid peptide activityGO:0001515

Processes

G protein-coupled opioid receptor signaling pathwayGO:0038003 adenylate cyclase-inhibiting opioid receptor signaling pathwayGO:0031635

Locations

extracellular regionGO:0005576

Endogenous opioid-related neuropeptide precursor processed into the heptadecapeptide nociceptin (orphanin FQ, bearing an N-terminal Phe-Gly-Gly-Phe message motif), which selectively binds and activates the nociceptin opioid receptor OPRL1 (NOP) to initiate Gi/o-coupled adenylate cyclase-inhibiting signaling.

Reactome:R-HSA-418594
G alpha (i) signalling events
Establishes that PNOC-derived nociceptin activates Gi/o-coupled OPRL1 to inhibit adenylate cyclase.
The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002).
OPRM1 mu-type opioid receptor
oprm1_mu_opioid_receptor
Participant: Family: Mu-type opioid receptor subfamily
Family:
Mu-type opioid receptor subfamilyPANTHER:PTHR24229:SF7
Representative Members: OPRM1UniProtKB:P35372

Function

G protein-coupled opioid receptor activityGO:0004985

Processes

G protein-coupled opioid receptor signaling pathwayGO:0038003 adenylate cyclase-inhibiting opioid receptor signaling pathwayGO:0031635

Locations

plasma membraneGO:0005886

Seven-transmembrane Gi/o-coupled mu-type opioid receptor activated by PENK-derived enkephalins and beta-endorphin to inhibit adenylate cyclase.

Reactome:R-HSA-374298
Opioid receptors bind opioid peptides
Establishes OPRM1 as a Gi/o-coupled opioid receptor inhibiting adenylate cyclase.
The mu-opioid receptor (MOR) (Wang JB et al, 1994) possesses high affinity for enkephalins and beta-endorphin but low affinity for dynorphins.
OPRD1 delta-type opioid receptor
oprd1_delta_opioid_receptor
Participant: Family: Delta-type opioid receptor subfamily
Family:
Delta-type opioid receptor subfamilyPANTHER:PTHR24229:SF2
Representative Members: OPRD1UniProtKB:P41143

Function

G protein-coupled opioid receptor activityGO:0004985

Processes

G protein-coupled opioid receptor signaling pathwayGO:0038003 adenylate cyclase-inhibiting opioid receptor signaling pathwayGO:0031635

Locations

plasma membraneGO:0005886

Seven-transmembrane Gi/o-coupled delta-type opioid receptor preferentially activated by PENK-derived Met- and Leu-enkephalins to inhibit adenylate cyclase.

Reactome:R-HSA-374298
Opioid receptors bind opioid peptides
Establishes OPRD1 as a Gi/o-coupled opioid receptor inhibiting adenylate cyclase.
Enkephalins are pentapeptides involved in regulating pain and nociception in the body. Their action is mediated through the delta-opioid receptor (DOR) (Knapp RJ et al, 1994).
OPRK1 kappa-type opioid receptor
oprk1_kappa_opioid_receptor
Participant: Family: Kappa-type opioid receptor subfamily
Family:
Kappa-type opioid receptor subfamilyPANTHER:PTHR24229:SF1
Representative Members: OPRK1UniProtKB:P41145

Function

G protein-coupled opioid receptor activityGO:0004985

Processes

G protein-coupled opioid receptor signaling pathwayGO:0038003 adenylate cyclase-inhibiting opioid receptor signaling pathwayGO:0031635

Locations

plasma membraneGO:0005886

Seven-transmembrane Gi/o-coupled kappa-type opioid receptor preferentially activated by PDYN-derived dynorphins to inhibit adenylate cyclase.

PMID:9047294
NMR and structural model of dynorphin A (1-17) bound to dodecylphosphocholine micelles.
Establishes OPRK1 as the physiological receptor for dynorphin A.
Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand.
OPRL1 nociceptin opioid receptor (NOP)
oprl1_nociceptin_receptor
Participant: Family: Nociceptin receptor subfamily
Family:
Nociceptin receptor subfamilyPANTHER:PTHR24229:SF11
Representative Members: OPRL1UniProtKB:P41146

Function

G protein-coupled opioid receptor activityGO:0004985

Processes

G protein-coupled opioid receptor signaling pathwayGO:0038003 adenylate cyclase-inhibiting opioid receptor signaling pathwayGO:0031635

Locations

plasma membraneGO:0005886

Seven-transmembrane Gi/o-coupled nociceptin/orphanin FQ opioid receptor (NOP) selectively activated by PNOC-derived nociceptin to inhibit adenylate cyclase.

Reactome:R-HSA-111885
Opioid Signalling
Establishes OPRL1 as a Gi/o-coupled opioid-family receptor inhibiting adenylate cyclase.
Opioids receptors are G-protein coupled receptors (GPCR). There are four classes of receptors: mu (MOR), kappa (KOR) and delta (DOR), and the nociceptin receptor (NOP).
Part 2: Gi/o activation and adenylate cyclase inhibition
Gi/o activation and adenylate cyclase inhibition downstream of opioid receptorsRegulatory Stepopioid_gi_adenylate_cyclase_inhibition

Agonist-activated OPRM1, OPRD1, OPRK1, and OPRL1 catalyze GDP-to-GTP exchange on pertussis-toxin-sensitive inhibitory Gi/o alpha subunits (exemplified by GNAI1), which directly inhibit membrane-bound adenylate cyclases (exemplified by ADCY5) to lower intracellular cAMP levels.

Annotons

GNAI1 Gi alpha-1 subunit
gnai1_gi_alpha
Participant: Family: Guanine nucleotide-binding protein G(i) subunit alpha-1 subfamily
Family:
Guanine nucleotide-binding protein G(i) subunit alpha-1 subfamilyPANTHER:PTHR10218:SF359
Representative Members: GNAI1UniProtKB:P63096

Function

G protein activityGO:0003925

Processes

G protein-coupled opioid receptor signaling pathwayGO:0038003 adenylate cyclase-inhibiting opioid receptor signaling pathwayGO:0031635

Locations

plasma membraneGO:0005886

Inhibitory Gi alpha subunit activated by ligand-bound opioid receptors to inhibit adenylate cyclase.

Reactome:R-HSA-418594
G alpha (i) signalling events
Establishes that activated Gi/o alpha subunits signal by inhibiting adenylate cyclase.
The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002).
ADCY5 adenylate cyclase type 5 effector
adcy5_adenylate_cyclase
Participant: Family: Adenylate cyclase type 5 subfamily
Family:
Adenylate cyclase type 5 subfamilyPANTHER:PTHR45627:SF7
Representative Members: ADCY5UniProtKB:O95622

Function

adenylate cyclase activityGO:0004016

Processes

G protein-coupled opioid receptor signaling pathwayGO:0038003 adenylate cyclase-inhibiting opioid receptor signaling pathwayGO:0031635

Locations

plasma membraneGO:0005886

Membrane-bound adenylate cyclase effector inhibited by GTP-bound Gi/o alpha subunits downstream of opioid receptor activation.

Reactome:R-HSA-418594
G alpha (i) signalling events
Demonstrates adenylate cyclase inhibition as the canonical effector step of activated Gi/o alpha subunits.
The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002).