Regulation of voltage-gated Ca2+ channels by lipids.

Article Details

Citation

Roberts-Crowley ML, Mitra-Ganguli T, Liu L, Rittenhouse AR

Regulation of voltage-gated Ca2+ channels by lipids.

Cell Calcium. 2009 Jun;45(6):589-601. doi: 10.1016/j.ceca.2009.03.015. Epub 2009 May 6.

PubMed ID
19419761 [ View in PubMed
]
Abstract

Great skepticism has surrounded the question of whether modulation of voltage-gated Ca(2+) channels (VGCCs) by the polyunsaturated free fatty acid arachidonic acid (AA) has any physiological basis. Here we synthesize findings from studies of both native and recombinant channels where micromolar concentrations of AA consistently inhibit both native and recombinant activity by stabilizing VGCCs in one or more closed states. Structural requirements for these inhibitory actions include a chain length of at least 18 carbons and multiple double bonds located near the fatty acid's carboxy terminus. Acting at a second site, AA increases the rate of VGCC activation kinetics, and in Ca(V)2.2 channels, increases current amplitude. We present evidence that phosphatidylinositol 4,5-bisphosphate (PIP(2)), a palmitoylated accessory subunit (beta(2a)) of VGCCs and AA appear to have overlapping sites of action giving rise to complex channel behavior. Their actions converge in a physiologically relevant manner during muscarinic modulation of VGCCs. We speculate that M(1) muscarinic receptors may stimulate multiple lipases to break down the PIP(2) associated with VGCCs and leave PIP(2)'s freed fatty acid tails bound to the channels to confer modulation. This unexpectedly simple scheme gives rise to unanticipated predictions and redirects thinking about lipid regulation of VGCCs.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Fish oilVoltage gated L-type calcium channel (Protein Group)Protein groupHumans
Unknown
Inhibitor
Details