OPRM1 (mu-type opioid receptor, MOR, P35372) — curation notes

Deep research status (2026-10-15)

Automated deep research could not be generated for this review:

• just deep-research-falcon human OPRM1 --fallback openai: the Edison/Falcon
  auth endpoint returned 503 Service Unavailable ("Failed to authenticate"),
  and the OpenAI fallback returned 401 invalid_api_key. A second Falcon attempt
  failed the same way.
• just deep-research human OPRM1 --provider perplexity: provider not available
  in this environment (Provider 'perplexity' not available. Available: openai, falcon, openscientist).

No -deep-research-*.md file exists. The literature synthesis below was done
manually from the GOA-cited publications (cached by just fetch-gene) plus a
small set of additional key papers fetched with just fetch-pmid and checked
against their cached titles: PMID:8893006 (Oprm1 knockout), PMID:10617462
(beta-arrestin 2 knockout), PMID:22437502, PMID:26245379, PMID:29899455
(receptor structures) and PMID:27533032 (PZM21, G protein-biased agonist).

Identity and family

• Class A (rhodopsin-like) GPCR; UniProt: "Belongs to the G protein-coupled
  receptor 1 family." InterPro: Mu_opioid_rcpt (IPR000105), Opioid_rcpt
  (IPR001418). Paralogs OPRD1, OPRK1, OPRL1.
• Many splice isoforms (18 named in UniProt), including 6TM MOR1K (isoform 12)
  and binding-incompetent SV1/SV2 (isoforms 16, 17).

Molecular function: opioid receptor activity

• Human MOR was cloned and shown to bind opiates and opioid peptides in a
  G protein-sensitive way PMID:7905839.
• Mu-selective high-affinity binding PMID:7891175; splice variants hMOR-1O/1X keep mu selectivity
  PMID:12589820.
• Endogenous ligand beta-endorphin: the A118G (N40D) variant changes
  beta-endorphin binding and potency PMID:9689128.
• UniProt FUNCTION: "Receptor for endogenous opioids such as beta-endorphin and
  endomorphin" and "Receptor for natural and synthetic opioids including morphine,
  heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone"; enkephalins
  "By similarity".
• In vivo, MOR is the mandatory target of morphine [PMID:8893006 "a lack of mu
  receptors abolishes the analgesic effect of morphine, as well as
  place-preference activity and physical dependence"; "the mu-opioid-receptor
  gene product is the molecular target of morphine in vivo"].
• Structures (mouse receptor): antagonist-bound crystal PMID:22437502,
  agonist + G protein mimetic nanobody PMID:26245379, DAMGO-MOR-Gi cryo-EM
  PMID:29899455.

Signaling (Gi/o arm)

• Adenylyl cyclase inhibition by human MOR in heterologous cells
  PMID:14573758
  PMID:19788913 PMID:7957926.
• G beta-gamma effectors: GIRK activation PMID:7891175;
  UniProt also lists inhibition of N- and L-type Ca channels, PLC, MAPK (mostly By
  similarity). MOR does not itself have channel activity; the ISS "voltage-gated
  calcium channel activity" row confuses an effector with the receptor.
• Canonical MOR1 couples to Gi/o, whereas the 6TM MOR1K isoform couples to Gs
  and is retained intracellularly PMID:20525224.

Regulation: GRK / beta-arrestin, desensitization, bias

• Kinase-modulated desensitization of human MOR PMID:7891175.
• beta-arrestin 2 limits morphine analgesia in vivo PMID:10617462.
• Biased ligands: PMID:27533032. Whether arrestin
  vs G protein signaling separates analgesia from respiratory depression is
  contested in later literature (not cached here); GO currently has no way to
  distinguish G protein-biased from arrestin-dependent MOR signaling.
• Interactors modulating trafficking: filamin A PMID:14573758, RanBPM PMID:19788913,
  WLS/GPR177 PMID:20214800.

Location

• Plasma membrane (multiple EXP papers; UniProt "Cell membrane"); neuronal
  axon, dendrite, perikaryon, endosome by similarity to guinea pig OPRM1 (P97266; the rodent ISS donor is guinea pig, while the GO_REF:0000107 IEA donor P42866 is mouse); "Is rapidly
  internalized after agonist binding".

Annotation-review judgements (summary)

• GO:0004930 GPCR activity -> MODIFY to morphine receptor activity
  (GO:0038047) and beta-endorphin receptor activity (GO:0004979).
• Generic GPCR signaling / cyclic-nucleotide / ACh-pathway rows -> MODIFY to
  GO:0031635 adenylate cyclase-inhibiting opioid receptor signaling pathway
  (is_a GO:0007193 and GO:0038003, checked in OLS).
• voltage-gated calcium channel activity (ISS from rat P33535) and the derived
  IEA calcium ion transmembrane transport -> REMOVE (receptor inhibits channels;
  it is not a channel).
• 21 protein binding IPI rows -> REMOVE as uninformative (interactions not
  disputed).
• PMID:21039637 (human craving genetics, abstract-only): stress-induced craving
  result in the abstract is for CRH-BP, OPRM1 is associated with cue-induced
  craving; "regulation of cellular response to stress" left UNDECIDED.
• ER/Golgi TAS rows from PMID:9242668 (insect-cell overexpression, abstract
  only, abstract does not mention these compartments) left UNDECIDED.

Review round 2 (PR #5042) additions

• PENK peptide (P01210-PRO_0000008243) IPI row: UniProt "P35372; PRO_0000008243
  [P01210]: PENK; NbExp=3"; MODIFY to GO:0004985 (endogenous opioid peptide
  ligand), not REMOVE.
• Mouse sources traced via QuickGO for P42866: GO:0050769 IMP
  PMID:16682964; GO:0098982 SynGO PMID:31818459.
• Ethanol: PMID:10869404.

2026-10-31: merge with parallel review (PR #5350)

A second, independent review of OPRM1 was made in PR #5350. This review (#5042) is kept
as the base. Ported from #5350: PMID:42870023 (Deutsch et al. 2026, Nat Struct Mol
Biol), which used mouse μOR coupled to human Gαi1β1γ2 and shows that agonist efficacy
is encoded in how fast the Gi α-helical domain opens for GDP release PMID:42870023. Added as a reference, with two suggested questions and one suggested
experiment on whether this holds for human OPRM1 and its N40D variant.