GSBS Student Publications
Title
Regulation of voltage-gated Ca2+ channels by lipids
GSBS Program
Neuroscience
UMMS Affiliation
Department of Physiology
Date
5-8-2009
Document Type
Article
Medical Subject Headings
Arachidonic Acid; Calcium; Calcium Channels; GTP-Binding Protein alpha Subunits, Gq-G11; Lipids; Phosphatidylinositol 4,5-Diphosphate; Phospholipases A2, Cytosolic; Receptors, Muscarinic
Disciplines
Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology
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.
Rights and Permissions
Citation: Cell Calcium. 2009 Jun;45(6):589-601. Epub 2009 May 6. Link to article on publisher's site
DOI of Published Version
10.1016/j.ceca.2009.03.015
Related Resources
Journal Title
Cell calcium
PubMed ID
19419761
Repository Citation
Roberts-Crowley, Mandy L.; Ganguli, Tora Mitra; Liu, Liwang; and Rittenhouse, Ann R., "Regulation of voltage-gated Ca2+ channels by lipids" (2009). GSBS Student Publications. 1718.
https://escholarship.umassmed.edu/gsbs_sp/1718