Biological role
CB1R modulates neurotransmitter release and participates in membrane signaling across central and peripheral physiological contexts. Effects depend on tissue, cellular state, ligand, and experimental design.
OVERVIEW
Biology and structural analysis
In Homo sapiens,
cannabinoid receptor type 1 (CB1R) is
encoded by the protein-coding gene CNR1,
located at chromosome region 6q15. The reviewed human protein record
UniProtKB P21554 describes a 472-amino-acid integral membrane
protein in the class A family of G protein-coupled receptors. Its
characteristic topology comprises seven transmembrane segments.
Anandamide (N-arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG) are among its best-characterized endogenous ligands. CB1R predominantly couples to Gi/o-family G proteins. One major consequence is inhibition of adenylyl cyclase, which reduces the conversion of ATP to cyclic AMP (cAMP). This is not the receptor's only signaling route: CB1R can also modulate ion channels, protein-kinase pathways, and beta-arrestin-dependent responses according to ligand, cell type, and physiological context.
Comparative context
CNR1 orthologs enable explicit tests of sequence, structure, and functional conservation after speciation. Orthology supports a comparative hypothesis; it does not guarantee identical function.
Structural state
Experimentally determined structures capture selected receptor conformations. Comparing inactive, active, ligand-bound, and G-protein-coupled states supports mechanistic interpretation.
CURATED PROTEIN RECORD
UniProtKB P21554: human cannabinoid receptor 1
The record linked below is an external, versioned scientific resource maintained by UniProt. It should be read as a protein record, not merely as an amino-acid sequence. Database annotations can change; record identity and access context must therefore be preserved when a claim is reused.
| Entity | Curated value | Evidence context |
|---|---|---|
| Gene | CNR1 · NCBI Gene 1268 · 6q15 |
Human gene annotation and genomic location |
| Protein | UniProtKB P21554 · 472 amino acids | Reviewed human protein record |
| Receptor class | Class A GPCR · seven transmembrane segments | Curated topology and pharmacological classification |
| Endogenous ligands | Anandamide and 2-AG | Key endogenous ligands; the list is not exhaustive |
Curated against NCBI Gene 1268, IUPHAR/BPS Guide to Pharmacology, and UniProtKB P21554. Sources accessed 12 July 2026.
EXTERNAL CURATED RECORD
UniProtKB P21554 · CNR1_HUMAN
Open the current reviewed entry at its source when checking sequence, topology, functional annotations, cross-references, evidence status, or record history.
The external resource opens in a dedicated tab so UniProt can run in its supported browsing context. Confirm the accession and record version before reusing an annotation.
RECEPTOR CLASSIFICATION
CB1 and CB2 within the rhodopsin-like GPCR class
Cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2
(CB2), encoded by CNR1 and CNR2
respectively, belong to class A of the G protein-coupled receptor
superfamily. Class A is also known as the rhodopsin-like receptor
family and provides the broader structural and evolutionary context
for interpreting cannabinoid receptors.
G protein-coupled receptors
Class A / rhodopsin-like receptors
Cannabinoid receptors
CB1 · CNR1
CB2 · CNR2
Historical phylogenetic subdivision
A 2002 phylogenetic analysis proposed subdivision of the rhodopsin-like group into 19 subfamilies. This is useful as a historical classification derived from a particular method and taxonomic sample; it should not be treated as a universal or definitive GPCR taxonomy.
Scope for this CB1R page
The class A assignment supports receptor-level comparison, but it does not by itself establish CB1-specific physiology, functional conservation across species, orthology, or the evolutionary history of cannabinoid signaling.
CURATED PATHWAY RECORD
Reactome: cannabinoid receptors can bind cannabinoids
Reactome places the human cannabinoid-receptor binding event within Signal Transduction → Signaling by GPCR → GPCR ligand binding → Class A/1 (rhodopsin-like receptors). The event aggregates cannabinoid receptors and therefore provides pathway and classification context rather than CB1-only evidence.
Source: Reactome R-HSA-419426. Cross-check receptor nomenclature with the IUPHAR/BPS cannabinoid receptor family.
EVOLUTION
From an ancestral chordate receptor to vertebrate CB1 and CB2
The evolutionary history of canonical cannabinoid receptors is most clearly reconstructed within Chordata. Comparative studies have identified a single CB1/CB2-type receptor in the urochordate Ciona intestinalis and the cephalochordate Branchiostoma floridae. These receptors are interpreted as descendants of a receptor present before the origin of the two vertebrate cannabinoid-receptor lineages.
Chordata
-
Urochordata ancestral CB1/CB2-type receptor
-
Cephalochordata ancestral CB1/CB2-type receptor
-
Vertebrata receptor-gene duplication and diversification
-
CNR1CB1 receptor lineage -
CNR2CB2 receptor lineage
-
A duplication in the vertebrate lineage is the leading explanation
for the emergence of the distinct CB1 and CB2 receptor families.
After that duplication, speciation generated CNR1
orthologs across vertebrate lineages. Those orthologs provide the
appropriate basis for testing conservation and diversification of
CB1 sequence, structure, expression, signaling, and physiology.
The ancestral chordate receptor should not be called CB1 or CB2 without qualification: it predates the duplication that separated those vertebrate receptor lineages. Likewise, the presence of an ortholog does not guarantee identical expression, pharmacology, or physiological function in every species.
READING GUIDE
Separate ancestry, duplication, and functional conservation
Similarity supports comparison, but evolutionary relationships require gene-tree and species-tree evidence. Functional conservation requires an additional layer of experimental or comparative physiological evidence.
Comparative basis: Elphick, 2012 and the identification of a CB1/CB2-type receptor ortholog in Branchiostoma floridae. These sources support a chordate origin for CB1/CB2-type receptors and subsequent vertebrate diversification; they do not establish identical receptor function across all chordates.
STRUCTURES
Which CB1R structures are most useful for comparison?
These experimental structures and coordinate models are used as editorial anchors for the page. Together, they show an inactive crystallographic reference, active receptor states, an endocannabinoid-analog complex, and an allosteric-modulator complex for controlled structural comparison.
Structural coordinates are obtained from the cited PDB records and rendered locally with 3Dmol.js. Use the official RCSB PDB Mol* viewer. Entry metadata accessed 12 July 2026. Experimental structures are snapshots produced under specific constructs and conditions; compare method, resolution, mutations, ligands, and validation reports before drawing mechanistic conclusions.
| PDB | Ligand | Comparative role |
|---|---|---|
| 5TGZ | AM6538 | Inactive antagonist-bound state |
| 5XRA | AM11542 | Active agonist-bound state |
| 5XR8 | AM841 | Active agonist-bound state |
| 5U09 | Taranabant | High-resolution inactive reference |
| 9B54 | VIP36 | Biased agonism in a CB1–Gi complex |
GUIDED COMPARISONS
Compare structures through explicit scientific questions
Select the cited PDB records in the 3D panel above and inspect them sequentially. Retain method, resolution, ligand, construct, and validation differences while moving between structures.
01 · INACTIVE STATES
5TGZ × 5U09
How do AM6538 and taranabant occupy the orthosteric pocket and stabilize experimentally observed inactive conformations?
Differences may reflect ligand, mutations, fusion partners, construct design, and crystallographic conditions.
02 · AGONIST EFFECTS
5XRA × 5XR8
Which contacts and pocket rearrangements are shared or ligand-specific for AM11542 and AM841?
Structural differences alone do not establish differences in efficacy, potency, or physiological response.
03 · SIGNALING COMPLEXES
6KPG × 8GHV × 9B54
How do receptor activation, Gi coupling, ligand context, and the biased-agonist complex differ among these snapshots?
Biased agonism depends on assay, pathway, cellular context, reference ligand, and quantitative transduction analysis.
04 · BINDING SITES
6KQI × orthosteric structures
Where is the allosteric site relative to orthosteric ligands, and which conformational connections are plausible?
Spatial proximity or conformational difference does not by itself establish physiological allosteric efficacy.
DOCKING
How can THC–CB1R binding poses be evaluated?
Docking proposes testable binding poses within a selected receptor structure; it does not demonstrate binding or efficacy by itself. Molecular dynamics can then test whether a modeled pose relaxes, persists, or shifts under the chosen simulation conditions.
THC is the plant-derived ligand used in this discussion. Docking results should be compared with experimentally determined CB1R complexes and evaluated alongside affinity, functional-assay, and simulation evidence. Similarity to another agonist does not prove that THC adopts the same pose or produces the same response.
A receptor is conformationally dynamic. Modeling is most useful when a simulated trajectory is compared with experimental structures while the construct, ligand, membrane, force field, and sampling limits remain explicit.
VIEWER PROMPTS
Analytical prompts
- What part of the pocket is conserved?
- Which ligand shape best matches the observed state?
- What motion remains stable over time?
CONCLUSION
A receptor page with a clear learning path
Scope
CB1R is used here as the receptor-side case study for vertebrate biology, signaling, and ligand-bound structural states.
Interpretation
The page keeps structure, evolution, and function connected so the reader can compare states without losing the biological context.
Next step
Return to Cannabis sativa for the species frame or use the docking section to evaluate hypotheses about THC–CB1R binding.
In this knowledge track, CB1R represents a vertebrate receptor that can be modulated by endogenous ligands and plant-derived cannabinoids. The species, enzyme, phytochemical, and receptor pages form a cross-kingdom evidence framework, not one continuous biological pathway and not evidence of direct Plantae–Animalia coevolution.
NEXT · REPRODUCIBLE LAB
Continue to the CB1R Structural Lab
The future Lab will connect receptor states, ligands, functional regions and authored PyMOL workflows to reproducible images, documented methods and versioned GitHub source code.
Planned module
Access will be enabled after the first reproducible code release.
HANDOFF
What this page hands off to the next workflow
Mode
Hybrid observatory + panel for vertebrate receptor biology and structural analysis.
What is transferred
Curated receptor states, ligand context, experimental structure references, and translational notes centered on CB1R as a promising therapeutic target.
Acceptance criteria
Keep the receptor as the organizing entity, preserve source traceability, distinguish experimental structure from interpretation, and maintain THC as the canonical fitocannabinoid ligand context for this module.