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Inhibition of human recombinant T‐type calcium channels by N ‐arachidonoyl 5‐HT
Author(s) -
Gilmore Andrew J,
Heblinski Marika,
Reynolds Aaron,
Kassiou Michael,
Connor Mark
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02047.x
Subject(s) - trpv1 , chemistry , anandamide , cannabinoid receptor , voltage dependent calcium channel , 5 ht receptor , biophysics , endocannabinoid system , patch clamp , transient receptor potential channel , receptor , calcium , pharmacology , biochemistry , agonist , serotonin , biology , organic chemistry
BACKGROUND AND PURPOSE N ‐arachidonoyl 5‐HT (NA‐5HT) has anti‐nociceptive effects reported to be mediated by inhibitory actions at the transient receptor potential vanilloid receptor 1 (TRPV1) and fatty acid amide hydrolase (FAAH). Anandamide and N ‐arachidonoyl dopamine (NA‐DA), endocannabinoids that activate TRPV1 or are metabolized by FAAH, also inhibit T‐type calcium channels ( I Ca ). T‐type I Ca are expressed by many excitable cells, including neurons involved in pain detection and processing. We sought to determine whether NA‐5HT also modulates T‐type I Ca . EXPERIMENTAL APPROACH Human recombinant T‐type I Ca (Ca V 3 channels) expressed in HEK 293 cells were examined using standard whole‐cell voltage‐clamp electrophysiology techniques. KEY RESULTS NA‐5HT completely inhibited Ca V 3 channels with a rank order of potency ( p EC 50 ) of Ca V 3.1 (7.4) > Ca V 3.3 (6.8) ≥ Ca V 3.2 (6.6). The effects of NA‐5HT were voltage‐dependent, and it produced significant hyperpolarizing shifts in Ca V 3 steady‐state inactivation relationships. NA‐5HT selectively affected Ca V 3.3 channel kinetics. CONCLUSIONS AND IMPLICATIONS NA‐5HT increases the steady‐state inactivation of Ca V 3 channels, reducing the number of channels available to open during depolarization. These effects occur at NA‐5HT concentrations at or below those at which NA‐5HT affects TRPV1 receptors and FAAH. NA‐5HT is one of the most potent inhibitors of T‐type I Ca described to date, and it is likely to exert some of its biological effects, including anti‐nociception, via inhibition of these channels.