Direct inhibition by cannabinoids of human 5‐HT 3A receptors: probable involvement of an allosteric modulatory site

Direct inhibition by cannabinoids of human 5‐HT 3A receptors: probable involvement of an... Excised outside‐out patches from HEK293 cells stably transfected with the human (h) 5‐HT3A receptor cDNA were used to determine the effects of cannabinoid receptor ligands on the 5‐HT‐induced current using the patch clamp technique. In addition, binding studies with radioligands for 5‐HT3 as well as for cannabinoid CB1 and CB2 receptors were carried out. The 5‐HT‐induced current was inhibited by the following cannabinoid receptor agonists (at decreasing order of potency): Δ9‐THC, WIN55,212‐2, anandamide, JWH‐015 and CP55940. The WIN55,212‐2‐induced inhibition was not altered by SR141716A, a CB1 receptor antagonist. WIN55,212‐3, an enantiomer of WIN55,212‐2, did not affect the 5‐HT‐induced current. WIN55,212‐2 did not change the EC50 value of 5‐HT in stimulating current, but reduced the maximum effect. The CB1 receptor ligand (3H)‐SR141716A and the CB1/CB2 receptor ligand (3H)‐CP55940 did not specifically bind to parental HEK293 cells. In competition experiments on membranes of HEK293 cells transfected with the h5‐HT3A receptor cDNA, WIN55,212‐2, CP55940, anandamide and SR141716A did not affect (3H)‐GR65630 binding, but 5‐HT caused a concentration dependent‐inhibition. In conclusion, cannabinoids stereoselectively inhibit currents through recombinant h5‐HT3A receptors independently of cannabinoid receptors. Probably the cannabinoids act allosterically at a modulatory site of the h5‐HT3A receptor. Thus the functional state of the receptor can be controlled by the endogenous ligand anandamide. This site is a potential target for new analgesic and antiemetic drugs. British Journal of Pharmacology (2002) 137, 589–596. doi:10.1038/sj.bjp.0704829 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Direct inhibition by cannabinoids of human 5‐HT 3A receptors: probable involvement of an allosteric modulatory site

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Publisher
Wiley
Copyright
2002 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0704829
pmid
12381672
Publisher site
See Article on Publisher Site

Abstract

Excised outside‐out patches from HEK293 cells stably transfected with the human (h) 5‐HT3A receptor cDNA were used to determine the effects of cannabinoid receptor ligands on the 5‐HT‐induced current using the patch clamp technique. In addition, binding studies with radioligands for 5‐HT3 as well as for cannabinoid CB1 and CB2 receptors were carried out. The 5‐HT‐induced current was inhibited by the following cannabinoid receptor agonists (at decreasing order of potency): Δ9‐THC, WIN55,212‐2, anandamide, JWH‐015 and CP55940. The WIN55,212‐2‐induced inhibition was not altered by SR141716A, a CB1 receptor antagonist. WIN55,212‐3, an enantiomer of WIN55,212‐2, did not affect the 5‐HT‐induced current. WIN55,212‐2 did not change the EC50 value of 5‐HT in stimulating current, but reduced the maximum effect. The CB1 receptor ligand (3H)‐SR141716A and the CB1/CB2 receptor ligand (3H)‐CP55940 did not specifically bind to parental HEK293 cells. In competition experiments on membranes of HEK293 cells transfected with the h5‐HT3A receptor cDNA, WIN55,212‐2, CP55940, anandamide and SR141716A did not affect (3H)‐GR65630 binding, but 5‐HT caused a concentration dependent‐inhibition. In conclusion, cannabinoids stereoselectively inhibit currents through recombinant h5‐HT3A receptors independently of cannabinoid receptors. Probably the cannabinoids act allosterically at a modulatory site of the h5‐HT3A receptor. Thus the functional state of the receptor can be controlled by the endogenous ligand anandamide. This site is a potential target for new analgesic and antiemetic drugs. British Journal of Pharmacology (2002) 137, 589–596. doi:10.1038/sj.bjp.0704829

Journal

British Journal of PharmacologyWiley

Published: Nov 1, 2002

References

  • The effects of cannabinoid on the brain
    AMERI, AMERI
  • Pharmacological comparison of human homomeric 5‐HT 3A receptors versus heteromeric 5‐HT 3A/3B receptors
    BRADY, BRADY; STANFORD, STANFORD; ALI, ALI; LIN, LIN; WILLIAMS, WILLIAMS; DUBIN, DUBIN; HOPE, HOPE; BARNES, BARNES
  • Direct inhibition of T‐type calcium channels by the endogenous cannabinoid anandamide
    CHEMIN, CHEMIN; MONTEIL, MONTEIL; PEREZ‐REYES, PEREZ‐REYES; NARGEOT, NARGEOT; LORY, LORY
  • Delta‐9‐tetrahydrocannabinol differentially suppresses cisplatin induced emesis and indices of motor function via cannabinoid CB(1) receptors in the least shrew
    DARMANI, DARMANI
  • Anatomical basis for cannabinoid‐induced antinociception as revealed by intracerebral microinjections
    MARTIN, MARTIN; COFFIN, COFFIN; ATTIAS, ATTIAS; BALINSKY, BALINSKY; TSOU, TSOU; WALKER, WALKER
  • The endocannabinoid anandamide is a direct and selective blocker of the background K (+) channel TASK‐1
    MAINGRET, MAINGRET; PATEL, PATEL; LAZDUNSKI, LAZDUNSKI; HONORE, HONORE
  • Pharmacology of cannabinoid CB 1 and CB 2 receptors
    PERTWEE, PERTWEE
  • Anandamide, an endogenous cannabinoid, inhibits Shaker‐related voltage‐gated K + channels
    POLING, POLING; ROGAWSKI, ROGAWSKI; SALEM, SALEM; VICINI, VICINI

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