CNR1_FELCA
ID CNR1_FELCA Reviewed; 472 AA.
AC O02777;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1997, sequence version 1.
DT 03-AUG-2022, entry version 116.
DE RecName: Full=Cannabinoid receptor 1;
DE Short=CB-R;
DE Short=CB1;
GN Name=CNR1;
OS Felis catus (Cat) (Felis silvestris catus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Feliformia; Felidae; Felinae; Felis.
OX NCBI_TaxID=9685;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND TISSUE SPECIFICITY.
RC TISSUE=Cerebral vascular smooth muscle;
RX PubMed=10362691; DOI=10.1152/ajpheart.1999.276.6.h2085;
RA Gebremedhin D., Lange A.R., Campbell W.B., Hillard C.J., Harder D.R.;
RT "Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to
RT inhibit L-type Ca2+ channel current.";
RL Am. J. Physiol. 276:H2085-H2093(1999).
CC -!- FUNCTION: G-protein coupled receptor for endogenous cannabinoids
CC (eCBs), including N-arachidonoylethanolamide (also called anandamide or
CC AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids,
CC such as delta(9)-tetrahydrocannabinol (THC). Mediates many cannabinoid-
CC induced effects, acting, among others, on food intake, memory loss,
CC gastrointestinal motility, catalepsy, ambulatory activity, anxiety,
CC chronic pain. Signaling typically involves reduction in cyclic AMP (By
CC similarity). In the hypothalamus, may have a dual effect on
CC mitochondrial respiration depending upon the agonist dose and possibly
CC upon the cell type. Increases respiration at low doses, while decreases
CC respiration at high doses. At high doses, CNR1 signal transduction
CC involves G-protein alpha-i protein activation and subsequent inhibition
CC of mitochondrial soluble adenylate cyclase, decrease in cyclic AMP
CC concentration, inhibition of protein kinase A (PKA)-dependent
CC phosphorylation of specific subunits of the mitochondrial electron
CC transport system, including NDUFS2. In the hypothalamus, inhibits
CC leptin-induced reactive oxygen species (ROS) formation and mediates
CC cannabinoid-induced increase in SREBF1 and FASN gene expression. In
CC response to cannabinoids, drives the release of orexigenic beta-
CC endorphin, not that of melanocyte-stimulating hormone alpha/alpha-MSH,
CC from hypothalamic POMC neurons, hence promoting food intake. In the
CC hippocampus, regulates cellular respiration and energy production in
CC response to cannabinoids. Involved in cannabinoid-dependent
CC depolarization-induced suppression of inhibition (DSI), a process in
CC which depolarization of CA1 postsynaptic pyramidal neurons mobilizes
CC eCBs, which retrogradely activate presynaptic CB1 receptors,
CC transiently decreasing GABAergic inhibitory neurotransmission. Also
CC reduces excitatory synaptic transmission (By similarity). In superior
CC cervical ganglions and cerebral vascular smooth muscle cells, inhibits
CC voltage-gated Ca(2+) channels in a constitutive, as well as agonist-
CC dependent manner (PubMed:10362691). In cerebral vascular smooth muscle
CC cells, inhibition of voltage-gated Ca(2+) channels leads to
CC vasodilation and decrease in vascular tone (PubMed:10362691). Induces
CC leptin production in adipocytes and reduces LRP2-mediated leptin
CC clearance in the kidney, hence participating in hyperleptinemia. In
CC adipose tissue, CNR1 signaling leads to increased expression of SREBF1,
CC ACACA and FASN genes. In the liver, activation by endocannabinoids
CC leads to increased de novo lipogenesis and reduced fatty acid
CC catabolism, associated with increased expression of SREBF1/SREBP-1,
CC GCK, ACACA, ACACB and FASN genes. May also affect de novo cholesterol
CC synthesis and HDL-cholesteryl ether uptake. Peripherally modulates
CC energy metabolism. In high carbohydrate diet-induced obesity, may
CC decrease the expression of mitochondrial dihydrolipoyl
CC dehydrogenase/DLD in striated muscles, as well as that of selected
CC glucose/ pyruvate metabolic enzymes, hence affecting energy expenditure
CC through mitochondrial metabolism. In response to cannabinoid
CC anandamide, elicits a pro-inflammatory response in macrophages, which
CC involves NLRP3 inflammasome activation and IL1B and IL18 secretion (By
CC similarity). In macrophages infiltrating pancreatic islets, this
CC process may participate in the progression of type-2 diabetes and
CC associated loss of pancreatic beta-cells (By similarity).
CC {ECO:0000250|UniProtKB:P21554, ECO:0000250|UniProtKB:P47746,
CC ECO:0000269|PubMed:10362691}.
CC -!- ACTIVITY REGULATION: Hemopressin, a peptide derived from hemoglobin
CC subunit alpha (HBA1 and/or HBA2), acts as an antagonist peptide:
CC hemopressin-binding efficiently blocks cannabinoid receptor CNR1 and
CC subsequent signaling. {ECO:0000250|UniProtKB:P21554}.
CC -!- SUBUNIT: Interacts (via C-terminus) with CNRIP1; this interaction
CC attenuates constitutive, but not agonist-dependent, inhibition of
CC voltage-gated Ca(2+) channels in neurons (By similarity). Associates
CC with G protein alpha subunits, including G(i) alpha-1/GNAI1, G(i)
CC alpha-3/GNAI3 and G(o)-alpha/GNAO1; palmitoylation is important for
CC interaction with GNAI3 and GNAO1 (By similarity).
CC {ECO:0000250|UniProtKB:P20272, ECO:0000250|UniProtKB:P21554}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P21554};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:P21554}. Membrane
CC raft {ECO:0000250|UniProtKB:P21554}. Mitochondrion outer membrane
CC {ECO:0000250|UniProtKB:P47746}. Cell projection, axon
CC {ECO:0000250|UniProtKB:P20272}. Presynapse
CC {ECO:0000250|UniProtKB:P20272}. Note=Unexpectedly, in the mitochondria,
CC the C-terminus is located in the mitochondrial intermembrane space, a
CC compartment topologically considered as extracellular. In canonical
CC seven-transmembrane G-protein coupled receptors, the C-terminus is
CC cytosolic (By similarity). Found on presynaptic axon terminals in some
CC GABAergic neurons in the somatosensory cortex (By similarity).
CC {ECO:0000250|UniProtKB:P20272, ECO:0000250|UniProtKB:P47746}.
CC -!- TISSUE SPECIFICITY: Expressed in cerebral arterial muscle cells and
CC cerebral cortex (at protein level). {ECO:0000269|PubMed:10362691}.
CC -!- PTM: Palmitoylation at Cys-415 is important for recruitment at plasma
CC membrane and lipid rafts and association with G protein alpha subunits.
CC {ECO:0000250|UniProtKB:P21554}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; U94342; AAB53440.1; -; mRNA.
DR RefSeq; NP_001009331.1; NM_001009331.1.
DR AlphaFoldDB; O02777; -.
DR SMR; O02777; -.
DR STRING; 9685.ENSFCAP00000011905; -.
DR GeneID; 493926; -.
DR KEGG; fca:493926; -.
DR CTD; 1268; -.
DR eggNOG; KOG3656; Eukaryota.
DR InParanoid; O02777; -.
DR TreeFam; TF330052; -.
DR Proteomes; UP000011712; Unplaced.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0030424; C:axon; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0098793; C:presynapse; IEA:UniProtKB-SubCell.
DR GO; GO:0004949; F:cannabinoid receptor activity; ISS:UniProtKB.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central.
DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0007188; P:adenylate cyclase-modulating G protein-coupled receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0038171; P:cannabinoid signaling pathway; IBA:GO_Central.
DR GO; GO:0019222; P:regulation of metabolic process; IBA:GO_Central.
DR InterPro; IPR000810; Canbinoid_rcpt_1.
DR InterPro; IPR002230; Cnbnoid_rcpt.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR PANTHER; PTHR22750:SF47; PTHR22750:SF47; 1.
DR Pfam; PF00001; 7tm_1; 1.
DR PIRSF; PIRSF037995; Cnoid_rcpt_1; 1.
DR PRINTS; PR00522; CANABINOID1R.
DR PRINTS; PR00362; CANNABINOIDR.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR SMART; SM01381; 7TM_GPCR_Srsx; 1.
DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cell projection; G-protein coupled receptor; Glycoprotein;
KW Lipoprotein; Membrane; Mitochondrion; Mitochondrion outer membrane;
KW Palmitate; Phosphoprotein; Receptor; Reference proteome; Synapse;
KW Transducer; Transmembrane; Transmembrane helix.
FT CHAIN 1..472
FT /note="Cannabinoid receptor 1"
FT /id="PRO_0000069313"
FT TOPO_DOM 1..116
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TRANSMEM 117..142
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TOPO_DOM 143..154
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TRANSMEM 155..175
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TOPO_DOM 176..187
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TRANSMEM 188..212
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TOPO_DOM 213..232
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TRANSMEM 233..255
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TOPO_DOM 256..273
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TRANSMEM 274..299
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TOPO_DOM 300..344
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TRANSMEM 345..365
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TOPO_DOM 366..377
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TRANSMEM 378..399
FT /note="Helical; Name=7"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT TOPO_DOM 400..472
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT REGION 2..23
FT /note="Required for mitochondrial localization"
FT /evidence="ECO:0000250|UniProtKB:P47746"
FT MOD_RES 425
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P47746"
FT MOD_RES 429
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P47746"
FT LIPID 415
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:P21554"
FT CARBOHYD 77
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 83
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
SQ SEQUENCE 472 AA; 52887 MW; A2774DBF8F2DAF34 CRC64;
MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK LGYFPQKFPL TSFRGSPFQE
KMTAGDNSQL VPADQVNITE FYNKSLSSYK ENEENIQCGE NFMDMECFMI LNPSQQLAIA
VLSLTLGTFT VLENLLVLCV ILHSRSLRCR PSYHFIGSLA VADLLGSVIF VYSFVDFHVF
HRKDSPNVFL FKLGGVTASF TASVGSLFLT AIDRYISIHR PLAYKKIVTR PKAVVAFCLM
WTIAIVIAVL PLLGWNCKKL QSVCSDIFPL IDETYLMFWI GVTSVLLLFI VYAYMYILWK
AHIHAVRMIQ RGTQKSIIIH TSEDGKVQVT RPDQARMDIR LAKTLVLILV VLIICWGPLL
AIMVYDVFGK MNKLIKTVFA FCSMLCLLNS TVNPIIYALR SKDLRHAFRS MFPSCEGTAQ
PLDNSMGDSD CLHKHANNTA NVHRAAENCI KNTVQIAKVT ISVSTNTSAK AL
