Ca(V) channels are multi-subunit protein complexes that enable inward cellular 
Ca(2+) currents in response to membrane depolarization. We recently described 
structure-function studies of the intracellular α1 subunit domain I-II linker, 
directly downstream of domain IS6. The results show the extent of the linker's 
helical structure to be subfamily dependent, as dictated by highly conserved 
primary sequence differences. Moreover, the difference in structure confers 
different biophysical properties, particularly the extent and kinetics of 
voltage and calcium-dependent inactivation. Timothy syndrome is a human genetic 
disorder due to mutations in the Ca(V)1.2 gene. Here, we explored whether 
perturbation of the I-II linker helical structure might provide a mechanistic 
explanation for a Timothy syndrome mutant's (human Ca(V)1.2 G406R equivalent) 
biophysical effects on inactivation and activation. The results are equivocal, 
suggesting that a full mechanistic explanation for this Timothy syndrome 
mutation requires further investigation.