title: Regulation of murine cardiac contractility by activation of α(1A)-adrenergic receptor-operated Ca(2+) entry.
abstract: OBJECTIVE
  Sympathetic regulation of cardiac contractility is mediated in part by α(1)-adrenergic receptors (ARs), and the α(1A)-subtype has been implicated in the pathogenesis of cardiac hypertrophy. However, little is known about α(1A)-AR signalling pathways in ventricular myocardium. The aim of this study was to determine the signalling pathway that mediates α(1A)-AR-coupled cardiac contractility.
  
  
  RESULTS
  Using a transgenic model of enhanced cardiac α(1A)-AR expression and signalling (α(1A)-H mice), we identified a receptor-coupled signalling pathway that enhances Ca(2+) entry and increases contractility. This pathway involves α(1A)-AR-activated translocation of Snapin and the transient receptor potential canonical 6 (TRPC6) channel to the plasma membrane. In ventricular cardiomyocytes from α(1A)-H and their non-transgenic littermates (or WTs), stimulation with α(1A)-AR-specific agonists resulted in increased [Ca(2+)](i), which was dose-related and proportional to the level of α(1A)-AR expression. Blockade of TRPC6 inhibited the α(1A)-AR-mediated increase in [Ca(2+)](i) and contractility. External Ca(2+) entry, underlying the [Ca(2+)](i) increase, was not due to store-operated Ca(2+) entry but to a receptor-operated mechanism of Ca(2+) entry resulting from α(1A)-AR activation.
  
  
  CONCLUSIONS
  These findings indicate that Ca(2+) entry via the α(1A)-AR-Snapin-TRPC6-pathway plays an important role in physiological regulation of cardiac contractility and may be an important target for augmenting cardiac performance.
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Lowy Packer Building, 405 Liverpool St, Darlinghurst, NSW 2010, Australia.
authors.forename: Marion C
authors.initials: MC
authors.lastname: Mohl
authors.forename: Siiri E
authors.initials: SE
authors.lastname: Iismaa
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Xiao
authors.forename: Oliver
authors.initials: O
authors.lastname: Friedrich
authors.forename: Soeren
authors.initials: S
authors.lastname: Wagner
authors.forename: Vesna
authors.initials: V
authors.lastname: Nikolova-Krstevski
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wu
authors.forename: Ze-Yan
authors.initials: ZY
authors.lastname: Yu
authors.forename: Michael
authors.initials: M
authors.lastname: Feneley
authors.forename: Diane
authors.initials: D
authors.lastname: Fatkin
authors.forename: David G
authors.initials: DG
authors.lastname: Allen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Graham
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D019556:COS Cells; D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006331:Heart Diseases / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D054799:Phospholipase C beta / Q000378:metabolism; D021381:Protein Transport; D034622:RNA Interference; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D013997:Time Factors; D014162:Transfection; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C547715:Adra1a protein, rat; D058646:Adrenergic alpha-1 Receptor Agonists; D018340:Receptors, Adrenergic, alpha-1; C498451:Snapin protein, mouse; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D033921:Vesicular Transport Proteins; C096351:transient receptor potential cation channel, subfamily C, member 1; D054799:Phospholipase C beta