The Cannabinoid-Like Compound, VSN16R, Acts on Large Conductance, Ca2+-Activated K+ Channels to Modulate Hippocampal CA1 Pyramidal Neuron Firing

Setareh Tabatabaee; David Baker; David L Selwood; Benjamin J Whalley; Gary J Stephens

doi:10.3390/ph12030104

The Cannabinoid-Like Compound, VSN16R, Acts on Large Conductance, Ca²⁺-Activated K⁺ Channels to Modulate Hippocampal CA1 Pyramidal Neuron Firing

Pharmaceuticals (Basel). 2019 Jul 4;12(3):104. doi: 10.3390/ph12030104.

Authors

Setareh Tabatabaee¹, David Baker², David L Selwood³, Benjamin J Whalley¹, Gary J Stephens⁴

Affiliations

¹ Reading School of Pharmacy, University of Reading, Reading RG6 6AP, UK.
² Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, London E1 4AT, UK.
³ Department of Medicinal Chemistry, UCL Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
⁴ Reading School of Pharmacy, University of Reading, Reading RG6 6AP, UK. g.j.stephens@reading.ac.uk.

Abstract

Large conductance, Ca²⁺-activated K⁺ (BK_Ca) channels are widely expressed in the central nervous system, where they regulate action potential duration, firing frequency and consequential neurotransmitter release. Moreover, drug action on, mutations to, or changes in expression levels of BK_Ca can modulate neuronal hyperexcitability. Amongst other potential mechanisms of action, cannabinoid compounds have recently been reported to activate BK_Ca channels. Here, we examined the effects of the cannabinoid-like compound (R,Z)-3-(6-(dimethylamino)-6-oxohex-1-en-1-yl)-N-(1-hydroxypropan-2-yl) benzamide (VSN16R) at CA1 pyramidal neurons in hippocampal ex vivo brain slices using current clamp electrophysiology. We also investigated effects of the BK_Ca channel blockers iberiotoxin (IBTX) and the novel 7-pra-martentoxin (7-Pra-MarTx) on VSN16R action. VSN16R (100 μM) increased first and second fast after-hyperpolarization (fAHP) amplitude, decreased first and second inter spike interval (ISI) and shortened first action potential (AP) width under high frequency stimulation protocols in mouse hippocampal pyramidal neurons. IBTX (100 nM) decreased first fAHP amplitude, increased second ISI and broadened first and second AP width under high frequency stimulation protocols; IBTX also broadened first and second AP width under low frequency stimulation protocols. IBTX blocked effects of VSN16R on fAHP amplitude and ISI. 7-Pra-MarTx (100 nM) had no significant effects on fAHP amplitude and ISI but, unlike IBTX, shortened first and second AP width under high frequency stimulation protocols; 7-Pra-MarTx also shortened second AP width under low frequency stimulation protocols. However, in the presence of 7-Pra-MarTx, VSN16R retained some effects on AP waveform under high frequency stimulation protocols; moreover, VSN16R effects were revealed under low frequency stimulation protocols. These findings demonstrate that VSN16R has effects in native hippocampal neurons consistent with its causing an increase in initial firing frequency via activation of IBTX-sensitive BK_Ca channels. The differential pharmacological effects described suggest that VSN16R may differentially target BK_Ca channel subtypes.

Keywords: 7-pra-martentoxin; BKCa channels; VSN16R; cannabinoid; hippocampal pyramidal neurons.

Grants and funding

MC_PC_13037/MRC_/Medical Research Council/United Kingdom