Inhibition of human recombinant T‐type calcium channels by N‐arachidonoyl 5‐HT

BACKGROUND AND PURPOSEN‐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_V3 channels) expressed in HEK 293 cells were examined using standard whole‐cell voltage‐clamp electrophysiology techniques.

KEY RESULTS NA‐5HT completely inhibited Ca_V3 channels with a rank order of potency (pEC₅₀) of Ca_V3.1 (7.4) > Ca_V3.3 (6.8) ≥ Ca_V3.2 (6.6). The effects of NA‐5HT were voltage‐dependent, and it produced significant hyperpolarizing shifts in Ca_V3 steady‐state inactivation relationships. NA‐5HT selectively affected Ca_V3.3 channel kinetics.

CONCLUSIONS AND IMPLICATIONS NA‐5HT increases the steady‐state inactivation of Ca_V3 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.

DOI: 10.1111/j.1476-5381.2012.02047.x

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