Title

Regulation of voltage-gated Ca2+ channels by lipids

Student Author(s)

Mandy Roberts-Crowley; Tora Mitra Ganguli

Academic Program

Neuroscience

UMMS Affiliation

Department of Physiology

Publication Date

2009-05-08

Document Type

Article

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.

DOI of Published Version

10.1016/j.ceca.2009.03.015

Source

Cell Calcium. 2009 Jun;45(6):589-601. Epub 2009 May 6. Link to article on publisher's site

Journal/Book/Conference Title

Cell calcium

Related Resources

Link to Article in PubMed

PubMed ID

19419761

Link to Full Text

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