title: Pacemaking through Ca2+ stores interacting as coupled oscillators via membrane depolarization.
abstract: This study presents an investigation of pacemaker mechanisms underlying lymphatic vasomotion. We tested the hypothesis that active inositol 1,4,5-trisphosphate receptor (IP(3)R)-operated Ca(2+) stores interact as coupled oscillators to produce near-synchronous Ca(2+) release events and associated pacemaker potentials, this driving action potentials and constrictions of lymphatic smooth muscle. Application of endothelin 1 (ET-1), an agonist known to enhance synthesis of IP(3), to quiescent lymphatic smooth muscle syncytia first enhanced spontaneous Ca(2+) transients and/or intracellular Ca(2+) waves. Larger near-synchronous Ca(2+) transients then occurred leading to global synchronous Ca(2+) transients associated with action potentials and resultant vasomotion. In contrast, blockade of L-type Ca(2+) channels with nifedipine prevented ET-1 from inducing near-synchronous Ca(2+) transients and resultant action potentials, leaving only asynchronous Ca(2+) transients and local Ca(2+) waves. These data were well simulated by a model of lymphatic smooth muscle with: 1), oscillatory Ca(2+) release from IP(3)R-operated Ca(2+) stores, which causes depolarization; 2), L-type Ca(2+) channels; and 3), gap junctions between cells. Stimulation of the stores caused global pacemaker activity through coupled oscillator-based entrainment of the stores. Membrane potential changes and positive feedback by L-type Ca(2+) channels to produce more store activity were fundamental to this process providing long-range electrochemical coupling between the Ca(2+) store oscillators. We conclude that lymphatic pacemaking is mediated by coupled oscillator-based interactions between active Ca(2+) stores. These are weakly coupled by inter- and intracellular diffusion of store activators and strongly coupled by membrane potential. Ca(2+) store-based pacemaking is predicted for cellular systems where: 1), oscillatory Ca(2+) release induces depolarization; 2), membrane depolarization provides positive feedback to induce further store Ca(2+) release; and 3), cells are interconnected. These conditions are met in a surprisingly large number of cellular systems including gastrointestinal, lymphatic, urethral, and vascular tissues, and in heart pacemaker cells.
authors.affiliation: Neuroscience Group, School of Biomedical Sciences, Faculty of Health, The University of Newcastle, Newcastle, Australia. mohammad.imtiaz@newcastle.edu.au
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Imtiaz
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hosaka
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: von der Weid
authors.forename: Melissa
authors.initials: M
authors.lastname: Crowe
authors.forename: Dirk F
authors.initials: DF
authors.lastname: van Helden
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D006168:Guinea Pigs; D042601:Lymphatic Vessels / Q000166:cytology / Q000378:metabolism; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000378:metabolism
chemical_list: D002118:Calcium