Abstract
Excitation-contraction (EC) coupling in skeletal muscle requires a physical interaction between the voltage-gated calcium channel, dihydropyridine receptor (DHPR), and the ryanodine receptor (RyR1) Ca2+ release channel. Although the exact mode of communication that links these two membrane proteins remains to be fully resolved, both the α1s and β1a subunits of DHPR are two of a select number of critical proteins involved in this process. A detailed in vitro interaction study of these two proteins reveals that their association occurs between the β1a SH3 domain and the polyproline motifs located in a critical region of the α1s II-III loop. We demonstrate that subtle changes in the composition of the β1a SH3 domain influences the ability of β proteins to bind to II-III loop proteins and investigate the effect of these changes on EC skeletal coupling. Furthermore, investigation into the composition of the II-III loop shows that previously identified amino acids demonstrated to be important in EC coupling are implicated in in vitro binding. In summary, we ascribe a role for the DHPR β1a which involves the engagement of its SH3 domain with the α1s II-III loop and propose a scenario whereby this interaction may facilitate skeletal muscle EC coupling.