The proximal and distal C-terminal tail domains of the CB1 cannabinoid receptor mediate G protein coupling.
The human CB1 cannabinoid receptor couples to G(i/o) proteins and inhibits neuronal voltage-gated Ca2+ channels. The role of the C-terminal tail of the CB1 cannabinoid receptor in G(i/o) protein coupling was examined using the superior cervical ganglion neuronal expression system. Deletion of the distal intracellular C-terminal tail (amino acids 418-472) slowed the kinetics and reduced the magnitude of Ca2+ channel inhibition. Deletion of the entire intracellular C-terminal tail (amino acids 401-472) abolished Ca2+ channel inhibition demonstrating the critical role of the proximal amino acids 401-417 of the C-terminal tail in G protein signaling. Expression of the C-terminal truncated receptors on the cell surface was examined using an N-terminal CB1 antibody. Both the C-terminal truncated receptors were expressed on the cell surface and were no different from wild type CB1 cannabinoid receptors. This study establishes that the proximal CB1 cannabinoid receptor intracellular C-terminal tail domain (amino acids 401-417) is critical for G(i/o) protein coupling and that the distal C-terminal tail domain (amino acids 418-472) profoundly modulates both the magnitude and kinetics of signal transduction. Thus, the C-terminal tail of the CB1 cannabinoid receptor has a wider role in G protein coupling than was previously thought.
Nie
J
J
Department of Pharmacology and Toxicology, Medical College of Georgia, Room CB3515, 1120 15th Street, Augusta, GA 30912-2300, USA.
Lewis
D L
DL
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005822:Genetic Vectors; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011955:Receptors, Drug / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D015220:Calcium Channels; D018076:DNA, Complementary; D010446:Peptide Fragments; D043882:Receptors, Cannabinoid; D011956:Receptors, Cell Surface; D011955:Receptors, Drug; D019204:GTP-Binding Proteins