title: Termination of calcium-induced calcium release by induction decay: an emergent property of stochastic channel gating and molecular scale architecture.
abstract: Calcium-induced calcium release (CICR) is an inherently regenerative process due to the Ca(2+)-dependent gating of ryanodine receptors (RyRs) in the sarco/endoplasmic reticulum (SR) and is critical for cardiac excitation-contraction coupling. This process is seen as Ca(2+) sparks, which reflect the concerted gating of groups of RyRs in the dyad, a specialised junctional signalling domain between the SR and surface membrane. However, the mechanism(s) responsible for the termination of regenerative CICR during the evolution of Ca(2+) sparks remain uncertain. Rat cardiac RyR gating was recorded at physiological Ca(2+), Mg(2+) and ATP levels and incorporated into a 3D model of the cardiac dyad which reproduced the time-course of Ca(2+) sparks, Ca(2+) blinks and Ca(2+) spark restitution. Model CICR termination was robust, relatively insensitive to the number of dyadic RyRs and automatic. This emergent behaviour arose from the rapid development and dissolution of nanoscopic Ca(2+) gradients within the dyad. These simulations show that CICR does not require intrinsic inactivation or SR calcium sensing mechanisms for stability and cessation of regeneration that arises from local control at the molecular scale via a process we call 'induction decay'.
authors.affiliation: Department of Physiology and Pharmacology, University of Bristol, Bristol BS9 1TH, UK.
authors.forename: D R
authors.initials: DR
authors.lastname: Laver
authors.forename: C H T
authors.initials: CH
authors.lastname: Kong
authors.forename: M S
authors.initials: MS
authors.lastname: Imtiaz
authors.forename: M B
authors.initials: MB
authors.lastname: Cannell
mesh_terms: D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000502:physiology; D020013:Calcium Signaling; D015640:Ion Channel Gating; D008051:Lipid Bilayers; D008954:Models, Biological; D009010:Monte Carlo Method; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry*
chemical_list: D008051:Lipid Bilayers; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium