Inositol-1,4,5-trisphosphate-dependent Ca(2+) signalling in cat atrial excitation-contraction coupling and arrhythmias

J Physiol. 2004 Mar 16;555(Pt 3):607-15. doi: 10.1113/jphysiol.2003.058529. Epub 2004 Jan 30.


Inositol-1,4,5-trisphosphate (IP(3))-dependent Ca(2+) release represents the major Ca(2+) mobilizing pathway responsible for diverse functions in non-excitable cells. In the heart, however, its role is largely unknown or controversial. In intact cat atrial myocytes, endothelin (ET-1) increased basal [Ca(2+)](i) levels, enhanced action potential-evoked [Ca(2+)](i) transients, caused [Ca(2+)](i) transients with alternating amplitudes (Ca(2+) alternans), and facilitated spontaneous Ca(2+) release from the sarcoplasmic reticulum (SR) in the form of Ca(2+) sparks and arrhythmogenic Ca(2+) waves. These effects were prevented by the IP(3) receptor (IP(3)R) blocker aminoethoxydiphenyl borate (2-APB), suggesting the involvement of IP(3)-dependent SR Ca(2+) release. In saponin-permeabilized myocytes IP(3) and the more potent IP(3)R agonist adenophostin increased basal [Ca(2+)](i) and the frequency of spontaneous Ca(2+) sparks. In the presence of tetracaine to eliminate Ca(2+) release from ryanodine receptor (RyR) SR Ca(2+) release channels, IP(3) and adenophostin triggered unique elementary, non-propagating IP(3)R-dependent Ca(2+) release events with amplitudes and kinetics that were distinctly different from classical RyR-dependent Ca(2+) sparks. The effects of IP(3) and adenophostin were prevented by heparin and 2-APB. The data suggest that IP(3)-dependent Ca(2+) release increases [Ca(2+)](i) in the vicinity of RyRs and thus facilitates Ca(2+)-induced Ca(2+) release during excitation-contraction coupling. It is concluded that in the adult mammalian atrium IP(3)-dependent Ca(2+) release enhances atrial Ca(2+) signalling and exerts a positive inotropic effect. In addition, by facilitating Ca(2+) release, IP(3) may also be an important component in the development of Ca(2+)-mediated atrial arrhythmias.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / physiopathology*
  • Atrial Function*
  • Calcium / metabolism
  • Calcium Channels / metabolism
  • Calcium Signaling* / drug effects
  • Cats
  • Endothelin-1 / pharmacology
  • Female
  • Heart Atria
  • Inositol 1,4,5-Trisphosphate / metabolism*
  • Inositol 1,4,5-Trisphosphate / pharmacology
  • Inositol 1,4,5-Trisphosphate Receptors
  • Intracellular Membranes / metabolism
  • Male
  • Myocardium / metabolism*
  • Myocytes, Cardiac / metabolism
  • Osmolar Concentration
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction


  • Calcium Channels
  • Endothelin-1
  • Inositol 1,4,5-Trisphosphate Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Inositol 1,4,5-Trisphosphate
  • Calcium