The voltage sensor of excitation–contraction coupling in mammals: Inactivation and interaction with Ca2+
| Autor: | Ferreira Gregorio, Juan, Pequera, Germán, Manno, Carlo, Ríos, Eduardo, Brum, Gustavo |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Physiology Muscle Fibers Skeletal Mice 03 medical and health sciences Extracellular medicine Animals Myocyte Calcium Signaling Research Articles Cells Cultured Excitation Contraction Coupling Calcium signaling RYR1 Mice Inbred BALB C Voltage-dependent calcium channel Chemistry Endoplasmic reticulum Skeletal muscle Ryanodine Receptor Calcium Release Channel Depolarization 030104 developmental biology medicine.anatomical_structure Biochemistry Biophysics Calcium Ion Channel Gating Research Article |
| Zdroj: | The Journal of General Physiology |
| ISSN: | 1540-7748 0022-1295 |
| DOI: | 10.1085/jgp.201611725 |
| Popis: | In excitation–contraction coupling, voltage-sensing modules (VSMs) of CaV1.1 Ca2+ channels simultaneously gate the associated pore and Ca2+ release channels in the sarcoplasmic reticulum. Ferreira Gregorio et al. find that VSMs adopt two inactivated states, and the degree of inactivation is dependent on external Ca2+ and the mouse strain used. In skeletal muscle, the four-helix voltage-sensing modules (VSMs) of CaV1.1 calcium channels simultaneously gate two Ca2+ pathways: the CaV1.1 pore itself and the RyR1 calcium release channel in the sarcoplasmic reticulum. Here, to gain insight into the mechanism by which VSMs gate RyR1, we quantify intramembrane charge movement associated with VSM activation (sensing current) and gated Ca2+ release flux in single muscle cells of mice and rats. As found for most four-helix VSMs, upon sustained depolarization, rodent VSMs lose the ability to activate Ca2+ release channels opening; their properties change from a functionally capable mode, in which the mobile sensor charge is called charge 1, to an inactivated mode, charge 2, with a voltage dependence shifted toward more negative voltages. We find that charge 2 is promoted and Ca2+ release inactivated when resting, well-polarized muscle cells are exposed to low extracellular [Ca2+] and that the opposite occurs in high [Ca2+]. It follows that murine VSMs are partly inactivated at rest, which establishes the reduced availability of voltage sensing as a pathogenic mechanism in disorders of calcemia. We additionally find that the degree of resting inactivation is significantly different in two mouse strains, which underscores the variability of voltage sensor properties and their vulnerability to environmental conditions. Our studies reveal that the resting and activated states of VSMs are equally favored by extracellular Ca2+. Promotion by an extracellular species of two states of the VSM that differ in the conformation of the activation gate requires the existence of a second gate, inactivation, topologically extracellular and therefore accessible from outside regardless of the activation state. |
| Databáze: | OpenAIRE |
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