scholarly journals STAC proteins associate to the IQ domain of CaV1.2 and inhibit calcium-dependent inactivation

2018 ◽  
Vol 115 (6) ◽  
pp. 1376-1381 ◽  
Author(s):  
Marta Campiglio ◽  
Pierre Costé de Bagneaux ◽  
Nadine J. Ortner ◽  
Petronel Tuluc ◽  
Filip Van Petegem ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Calcium Channel ◽  
Muscle Disease ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Calcium Dependent ◽  
C Terminus ◽  
Dependent Inactivation ◽  
C1 Domain

The adaptor proteins STAC1, STAC2, and STAC3 represent a newly identified family of regulators of voltage-gated calcium channel (CaV) trafficking and function. The skeletal muscle isoform STAC3 is essential for excitation–contraction coupling and its mutation causes severe muscle disease. Recently, two distinct molecular domains in STAC3 were identified, necessary for its functional interaction with CaV1.1: the C1 domain, which recruits STAC proteins to the calcium channel complex in skeletal muscle triads, and the SH3-1 domain, involved in excitation–contraction coupling. These interaction sites are conserved in the three STAC proteins. However, the molecular domain in CaV1 channels interacting with the STAC C1 domain and the possible role of this interaction in neuronal CaV1 channels remained unknown. Using CaV1.2/2.1 chimeras expressed in dysgenic (CaV1.1−/−) myotubes, we identified the amino acids 1,641–1,668 in the C terminus of CaV1.2 as necessary for association of STAC proteins. This sequence contains the IQ domain and alanine mutagenesis revealed that the amino acids important for STAC association overlap with those making contacts with the C-lobe of calcium-calmodulin (Ca/CaM) and mediating calcium-dependent inactivation of CaV1.2. Indeed, patch-clamp analysis demonstrated that coexpression of either one of the three STAC proteins with CaV1.2 opposed calcium-dependent inactivation, although to different degrees, and that substitution of the CaV1.2 IQ domain with that of CaV2.1, which does not interact with STAC, abolished this effect. These results suggest that STAC proteins associate with the CaV1.2 C terminus at the IQ domain and thus inhibit calcium-dependent feedback regulation of CaV1.2 currents.

scholarly journals Single-Channel Mechanism of Modulation of Calcium-Dependent Inactivation of the Voltage-Gated Calcium Channel Cav1.3 by its C-Terminus

2013 ◽  
Vol 104 (2) ◽  
pp. 459a
Author(s):  
Elena Novikova ◽  
Elza Kuzmenkina ◽  
Wanchana Jangsangthong ◽  
Jan Matthes ◽  
Alexandra Koschak ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Single Channel ◽  
Voltage Gated ◽  
Calcium Dependent ◽  
C Terminus ◽  
Dependent Inactivation ◽  
Voltage Gated Calcium Channel

scholarly journals Distinct roles for CaV1.1’s voltage-sensing domains

2021 ◽  
Vol 153 (11) ◽  
Author(s):  
Ben Short
Keyword(s):  
Skeletal Muscle ◽  
Calcium Channel ◽  
Voltage Sensing ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling

Study reveals how a slowly activating calcium channel is able to control rapid excitation–contraction coupling in skeletal muscle.

scholarly journals Functional properties of cardiac L-type calcium channels transiently expressed in HEK293 cells. Roles of alpha 1 and beta subunits.

1995 ◽  
Vol 105 (2) ◽  
pp. 289-305 ◽  
Author(s):  
M T Pérez-García ◽  
T J Kamp ◽  
E Marbán
Keyword(s):  
Skeletal Muscle ◽  
Calcium Channel ◽  
Binding Sites ◽  
Beta Subunit ◽  
Hek293 Cells ◽  
Beta Subunits ◽  
Calcium Dependent ◽  
Dependent Inactivation ◽  
Kinetics Of ◽  
Macroscopic Kinetics

The cardiac dihydropyridine-sensitive calcium channel was transiently expressed in HEK293 cells by transfecting the rabbit cardiac calcium channel alpha 1 subunit (alpha 1C) alone or in combination with the rabbit calcium channel beta subunit cloned from skeletal muscle. Transfection with alpha 1C alone leads to the expression of inward, voltage-activated, calcium or barium currents that exhibit dihydropyridine sensitivity and voltage- as well as calcium-dependent inactivation. Coexpression of the skeletal muscle beta subunit increases current density and the number of high-affinity dihydropyridine binding sites and also affects the macroscopic kinetics of the current. Recombinant alpha 1C beta channels exhibit a slowing of activation and a faster inactivation rate when either calcium or barium carries the charge. Our data suggest that both an increase in the number of channels as well as modulatory effects on gating underlie the modifications observed upon beta subunit coexpression.

scholarly journals Fast activation of dihydropyridine-sensitive calcium channels of skeletal muscle. Multiple pathways of channel gating.

1996 ◽  
Vol 108 (3) ◽  
pp. 221-232 ◽  
Author(s):  
J Ma ◽  
A González ◽  
R Chen
Keyword(s):  
Skeletal Muscle ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Voltage Sensor ◽  
Ca Channel ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Test Pulse ◽  
Fast Gating ◽  
Kinetics Of

Dihydropyridine (DHP) receptors of the transverse tubule membrane play two roles in excitation-contraction coupling in skeletal muscle: (a) they function as the voltage sensor which undergoes fast transition to control release of calcium from sarcoplasmic reticulum, and (b) they provide the conducting unit of a slowly activating L-type calcium channel. To understand this dual function of the DHP receptor, we studied the effect of depolarizing conditioning pulse on the activation kinetics of the skeletal muscle DHP-sensitive calcium channels reconstituted into lipid bilayer membranes. Activation of the incorporated calcium channel was imposed by depolarizing test pulses from a holding potential of -80 mV. The gating kinetics of the channel was studied with ensemble averages of repeated episodes. Based on a first latency analysis, two distinct classes of channel openings occurred after depolarization: most had delayed latencies, distributed with a mode of 70 ms (slow gating); a small number of openings had short first latencies, < 12 ms (fast gating). A depolarizing conditioning pulse to +20 mV placed 200 ms before the test pulse (-10 mV), led to a significant increase in the activation rate of the ensemble averaged-current; the time constant of activation went from tau m = 110 ms (reference) to tau m = 45 ms after conditioning. This enhanced activation by the conditioning pulse was due to the increase in frequency of fast open events, which was a steep function of the intermediate voltage and the interval between the conditioning pulse and the test pulse. Additional analysis demonstrated that fast gating is the property of the same individual channels that normally gate slowly and that the channels adopt this property after a sojourn in the open state. The rapid secondary activation seen after depolarizing prepulses is not compatible with a linear activation model for the calcium channel, but is highly consistent with a cyclical model. A six-state cyclical model is proposed for the DHP-sensitive Ca channel, which pictures the normal pathway of activation of the calcium channel as two voltage-dependent steps in sequence, plus a voltage-independent step which is rate limiting. The model reproduced well the fast and slow gating models of the calcium channel, and the effects of conditioning pulses. It is possible that the voltage-sensitive gating transitions of the DHP receptor, which occur early in the calcium channel activation sequence, could underlie the role of the voltage sensor and yield the rapid excitation-contraction coupling in skeletal muscle, through either electrostatic or allosteric linkage to the ryanodine receptors/calcium release channels.

Effect of the organic Ca2+ channel blocker D-600 on sarcoplasmic reticulum Ca2+ uptake in skeletal muscle

1997 ◽  
Vol 272 (1) ◽  
pp. C310-C317 ◽  
Author(s):  
A. Ortega ◽  
H. Gonzalez-Serratos ◽  
J. R. Lepock
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Calcium Channel ◽  
Channel Blocker ◽  
Inhibitory Effect ◽  
Blocking Effect ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Dose Dependent ◽  
Caffeine Exposure

Experiments were undertaken to study the possibility that the calcium channel blocker D-600 (gallopamil), which penetrates into muscle cells (20), facilitates excitation-contraction coupling in skeletal muscle (7) by a direct effect on the sarcoplasmic reticulum (SR). The effects of D-600 were studied on single phasic muscle fibers, either intact or split open. D-600 potentiated twitches in intact fibers at concentrations lower than those reported in whole muscles. In split fibers, the force produced by caffeine-induced Ca2+ release from the SR was reversibly inhibited by 5 microM D-600, when added to the Ca2+ loading solution. This inhibitory effect was inversely related to temperature, and it was dose dependent. When D-600 was added after Ca2+ loading and before caffeine exposure, or during the caffeine exposure itself, it did not inhibit Ca2+ release, but rather increased the development of force. We conclude that, apart from the blocking effect that D-600 may have on the voltage sensor, the drug penetrates into the myoplasm and affects excitation-contraction coupling by inhibiting the SR Ca2+ pump. This may be the consequence of a conformational change in the transmembrane Ca2+ binding domain of the ATPase.

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