title: Increased coupled gating of L-type Ca2+ channels during hypertension and Timothy syndrome.
abstract: BACKGROUND
  L-Type (Cav1.2) Ca(2+) channels are critical regulators of muscle and neural function. Although Cav1.2 channel activity varies regionally, little is known about the mechanisms underlying this heterogeneity.
  
  
  OBJECTIVE
  To test the hypothesis that Cav1.2 channels can gate coordinately.
  
  
  RESULTS
  We used optical and electrophysiological approaches to record Cav1.2 channel activity in cardiac, smooth muscle, and tsA-201 cells expressing Cav1.2 channels. Consistent with our hypothesis, we found that small clusters of Cav1.2 channels can open and close in tandem. Fluorescence resonance energy transfer and electrophysiological studies suggest that this coupling of Cav1.2 channels involves transient interactions between neighboring channels via their C termini. The frequency of coupled gating events increases in hypertensive smooth muscle and in cells expressing a mutant Cav1.2 channel that causes arrhythmias and autism in humans with Timothy syndrome (LQT8).
  
  
  CONCLUSIONS
  Coupled gating of Cav1.2 channels may represent a novel mechanism for the regulation of Ca(2+) influx and excitability in neurons, cardiac, and arterial smooth muscle under physiological and pathological conditions.
authors.affiliation: Department of Physiology & Biophysics, University of Washington-Seattle, 1705 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Navedo
authors.forename: Edward P
authors.initials: EP
authors.lastname: Cheng
authors.forename: Can
authors.initials: C
authors.lastname: Yuan
authors.forename: Scott
authors.initials: S
authors.lastname: Votaw
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
authors.forename: Luis F
authors.initials: LF
authors.lastname: Santana
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015640:Ion Channel Gating / Q000187:drug effects; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D054758:A Kinase Anchor Proteins; C520665:Akap5 protein, mouse; C514350:CACNA1C protein, mouse; C504728:Cacna1c protein, rat; D020746:Calcium Channels, L-Type; D002147:Calmodulin; D020536:Enzyme Activators; C419385:L-type calcium channel alpha(1C); D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases