British journal of pharmacology · 2012
Inhibition of human recombinant T-type calcium channels by N-arachidonoyl 5-HT.
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Gilmore Andrew J, Heblinski Marika, Reynolds Aaron, Kassiou Michael, Connor Mark
Аннотация
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.
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.