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

Abstract:

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 (pEC(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.

journal_name

Br J Pharmacol

authors

Gilmore AJ,Heblinski M,Reynolds A,Kassiou M,Connor M

doi

10.1111/j.1476-5381.2012.02047.x

subject

Has Abstract

pub_date

2012-11-01 00:00:00

pages

1076-88

issue

5

eissn

0007-1188

issn

1476-5381

journal_volume

167

pub_type

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