title: Restoration of normal L-type Ca2+ channel function during Timothy syndrome by ablation of an anchoring protein.
abstract: BACKGROUND
  L-type Ca(2+) (Ca(V)1.2) channels shape the cardiac action potential waveform and are essential for excitation-contraction coupling in heart. A gain-of-function G406R mutation in a cytoplasmic loop of Ca(V)1.2 channels causes long QT syndrome 8 (LQT8), a disease also known as Timothy syndrome. However, the mechanisms by which this mutation enhances Ca(V)1.2-LQT8 currents and generates lethal arrhythmias are unclear.
  
  
  OBJECTIVE
  To test the hypothesis that the anchoring protein AKAP150 modulates Ca(V)1.2-LQT8 channel gating in ventricular myocytes.
  
  
  RESULTS
  Using a combination of molecular, imaging, and electrophysiological approaches, we discovered that Ca(V)1.2-LQT8 channels are abnormally coupled to AKAP150. A pathophysiological consequence of forming this aberrant ion channel-anchoring protein complex is enhanced Ca(V)1.2-LQT8 currents. This occurs through a mechanism whereby the anchoring protein functions like a subunit of Ca(V)1.2-LQT8 channels that stabilizes the open conformation and augments the probability of coordinated openings of these channels. Ablation of AKAP150 restores normal gating in Ca(V)1.2-LQT8 channels and protects the heart from arrhythmias.
  
  
  CONCLUSIONS
  We propose that AKAP150-dependent changes in Ca(V)1.2-LQT8 channel gating may constitute a novel general mechanism for Ca(V)1.2-driven arrhythmias.
authors.affiliation: Department of Physiology & Biophysics, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Cheng
authors.forename: Can
authors.initials: C
authors.lastname: Yuan
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Navedo
authors.forename: Rose E
authors.initials: RE
authors.lastname: Dixon
authors.forename: Madeline
authors.initials: M
authors.lastname: Nieves-Cintrón
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 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000200:Action Potentials / Q000502:physiology; D000367:Age Factors; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D001321:Autistic Disorder; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015640:Ion Channel Gating / Q000502:physiology; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000502:physiology*; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D013576:Syndactyly / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D054758:A Kinase Anchor Proteins; C520665:Akap5 protein, mouse; C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D002118:Calcium