Abstract
Calcium for contraction of skeletal muscles is released via tetrameric ryanodine receptor (RYR1) channels of the sarcoplasmic reticulum (SR), which are assembled in ordered arrays called couplons at junctions where the SR abuts T tubules or plasmalemma. Voltage-gated Ca2+ (CaV1.1) channels, found in tubules or plasmalemma, form symmetric complexes called CaV tetrads that associate with and activate underlying RYR tetramers during membrane depolarization by conveying a conformational change. Intriguingly, CaV tetrads regularly skip every other RYR tetramer within the array; therefore, the RYRs underlying tetrads (named V), but not the voltage sensor-lacking (C) RYRs, should be activated by depolarization. Here we hypothesize that the checkerboard association is maintained solely by reversible binary interactions between CaVs and RYRs and test this hypothesis using a quantitative model of the energies that govern CaV1.1-RYR1 binding, which are assumed to depend on number and location of bound CaVs. A Monte Carlo simulation generates large statistical samples and distributions of state variables that can be compared with quantitative features in freeze-fracture images of couplons from various sources. This analysis reveals two necessary model features: (1) the energy of a tetramer must have wells at low and high occupation by CaVs, so that CaVs positively cooperate in binding RYR (an allosteric effect), and (2) a large energy penalty results when two CaVs bind simultaneously to adjacent RYR protomers in adjacent tetramers (a steric clash). Under the hypothesis, V and C channels will eventually reverse roles. Role reversal justifies the presence of sensor-lacking C channels, as a structural and functional reserve for control of muscle contraction.
Highlights
The contraction of striated muscles is activated by calcium ions released from the sarcoplasmic reticulum (SR) in response to membrane depolarization
We propose that CaV1.1–RYR1 interactions determine the checkerboard pattern, without invoking structures, interactions, or influences outside the couplon
We found that the checkerboard arrangement of tetrads could only be approximated by models that combined a strong steric effect with an allosteric effect, or positive cooperativity, whereby binding at one protomer was favored by binding to the other protomers in the same tetramer
Summary
The contraction of striated muscles is activated by calcium ions released from the sarcoplasmic reticulum (SR) in response to membrane depolarization. High values of f(4) in configurations of low bias reflect similar occupancies in odd and even channels, with o values of 4 or 0 still predominant at both locations Extrapolated to observations, this property of the model suggests that the complete tetrads found in junctions might not necessarily be placed on alternating RYR channels. The measures of occupancy obtained as described above were compared with outcomes of two-row couplon simulations Because this analysis of T tubule images was possible in a limited number of cases, we compared with numbers derived by Linsley et al (2017) in a study of zebrafish muscle.
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