Magnesium Inhibition of Ryanodine-Receptor Calcium Channels: Evidence for Two Independent Mechanisms |
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Authors: | DR Laver TM Baynes AF Dulhunty |
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Institution: | (1) Muscle Research Group, Division of Neuroscience, John Curtin School of Medical Research, Australian National University, GPO Box 334, Canberra, ACT 2601, Australia, AU |
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Abstract: | The gating of ryanodine receptor calcium release channels (RyRs) depends on myoplasmic Ca2+ and Mg2+ concentrations. RyRs from skeletal and cardiac muscle are activated by μm Ca2+ and inhibited by mm Ca2+ and Mg2+. 45Ca2+ release from skeletal SR vesicles suggests two mechanisms for Mg2+-inhibition (Meissner, Darling & Eveleth, 1986, Biochemistry
25:236–244). The present study investigates the nature of these mechanisms using measurements of single-channel activity from
cardiac- and skeletal RyRs incorporated into planar lipid bilayers.
Our measurements of Mg2+- and Ca2+-dependent gating kinetics confirm that there are two mechanisms for Mg2+ inhibition (Type I and II inhibition) in skeletal and cardiac RyRs. The mechanisms operate concurrently, are independent
and are associated with different parts of the channel protein. Mg2+ reduces P
o
by competing with Ca2+ for the activation site (Type-I) or binding to more than one, and probably two low affinity inhibition sites which do not
discriminate between Ca2+ and Mg2+ (Type-II). The relative contributions of the two inhibition mechanisms to the total Mg2+ effect depend on cytoplasmic Ca2+] in such a way that Mg2+ inhibition has the properties of Types-I and II inhibition at low and high Ca2+] respectively. Both mechanisms are equally important when Ca2+] = 10 μm in cardiac RyRs or 1 μm in skeletal RyRs. We show that Type-I inhibition is not the sole mechanism responsible for Mg2+ inhibition, as is often assumed, and we discuss the physiological implications of this finding.
Received: 1 January 1996/Revised: 14 November 1996 |
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Keywords: | : Magnesium inhibition — Calcium inhibition — Sarcoplasmic reticulum — Cardiac muscle — Skeletal muscle — Ryanodine receptor — Artificial BLM |
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