title: Ca2+ sparks act as potent regulators of excitation-contraction coupling in airway smooth muscle.
abstract: Ca2+ sparks are short lived and localized Ca2+ transients resulting from the opening of ryanodine receptors in sarcoplasmic reticulum. These events relax certain types of smooth muscle by activating big conductance Ca2+-activated K+ channels to produce spontaneous transient outward currents (STOCs) and the resultant closure of voltage-dependent Ca2+ channels. But in many smooth muscles from a variety of organs, Ca2+ sparks can additionally activate Ca2+-activated Cl(-) channels to generate spontaneous transient inward current (STICs). To date, the physiological roles of Ca2+ sparks in this latter group of smooth muscle remain elusive. Here, we show that in airway smooth muscle, Ca2+ sparks under physiological conditions, activating STOCs and STICs, induce biphasic membrane potential transients (BiMPTs), leading to membrane potential oscillations. Paradoxically, BiMPTs stabilize the membrane potential by clamping it within a negative range and prevent the generation of action potentials. Moreover, blocking either Ca2+ sparks or hyperpolarization components of BiMPTs activates voltage-dependent Ca2+ channels, resulting in an increase in global [Ca2+](i) and cell contraction. Therefore, Ca2+ sparks in smooth muscle presenting both STICs and STOCs act as a stabilizer of membrane potential, and altering the balance can profoundly alter the status of excitability and contractility. These results reveal a novel mechanism underlying the control of excitability and contractility in smooth muscle.
authors.affiliation: Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA. Ronghua.zhuge@umassmed.edu
authors.forename: Ronghua
authors.initials: R
authors.lastname: Zhuge
authors.forename: Rongfeng
authors.initials: R
authors.lastname: Bao
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Fogarty
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Lifshitz
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004553:Electric Conductivity; D005071:Evoked Potentials / Q000187:drug effects; D056966:Excitation Contraction Coupling / Q000187:drug effects; D007202:Indicators and Reagents / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008168:Lung; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D007202:Indicators and Reagents; D051036:Large-Conductance Calcium-Activated Potassium Channels; D002118:Calcium