title: L-type Ca2+ channel function during Timothy syndrome.
abstract: Voltage-gated, dihydropyridine-sensitive L-type Ca(2+) channels are multimeric proteins composed of a pore-forming transmembrane α(1) subunit (Ca(v)1.2) and accessory β, α(2)δ, and γ subunits. Ca(2+) entry via Ca(v)1.2 channels shapes the action potential (AP) of cardiac myocytes and is required for excitation-contraction coupling. Two de novo point mutations of Ca(v)1.2 glycine residues, G406R and G402S, cause a rare multisystem disorder called Timothy syndrome (TS). Here, we discuss recent work on the mechanisms by which Ca(v)1.2 channels bearing TS mutations display slowed inactivation that leads to increased Ca(2+) influx, prolonging the cardiac AP and promoting lethal arrhythmias. Based on these studies, we propose a model in which the scaffolding protein AKAP79/150 stabilizes the open conformation of Ca(v)1.2-TS channels and facilitates physical interactions among adjacent channels via their C-tails, increasing the activity of adjoining channels and amplifying Ca(2+) influx.
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Rose E
authors.initials: RE
authors.lastname: Dixon
authors.forename: Edward P
authors.initials: EP
authors.lastname: Cheng
authors.forename: Jose L
authors.initials: JL
authors.lastname: Mercado
authors.forename: Luis F
authors.initials: LF
authors.lastname: Santana
mesh_terms: D001321:Autistic Disorder; D020746:Calcium Channels, L-Type; D053447:Channelopathies / Q000473:pathology*; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D032383:Myocytes, Cardiac; D013576:Syndactyly / Q000235:genetics / Q000473:pathology*
chemical_list: D020746:Calcium Channels, L-Type