Calcium entry into excitable cells is an important physiological signal, 
supported by and highly sensitive to the activity of voltage-gated Ca2+ 
channels. After membrane depolarization, Ca2+ channels first open but then 
undergo various forms of negative feedback regulation including voltage- and 
calcium-dependent inactivation (VDI and CDI, respectively). Inactivation of Ca2+ 
channel activity is perturbed in a rare yet devastating disorder known as 
Timothy syndrome (TS), whose features include autism or autism spectrum disorder 
along with severe cardiac arrhythmia and developmental abnormalities. Most cases 
of TS arise from a sporadic single nucleotide change that generates a mutation 
(G406R) in the pore-forming subunit of the L-type Ca2+ channel Ca(V)1.2. We 
found that the TS mutation powerfully and selectively slows VDI while sparing or 
possibly speeding the kinetics of CDI. The deceleration of VDI was observed when 
the L-type channels were expressed with beta1 subunits prominent in brain, as 
well as beta2 subunits of importance for the heart. Dissociation of VDI and CDI 
was further substantiated by measurements of Ca2+ channel gating currents and by 
analysis of another channel mutation (I1624A) that hastens VDI, acting upstream 
of the step involving Gly406. As highlighted by the TS mutation, CDI does not 
proceed to completeness but levels off at approximately 50%, consistent with a 
change in gating modes and not an absorbing inactivation process. Thus, the TS 
mutation offers a unique perspective on mechanisms of inactivation as well as a 
promising starting point for exploring the underlying pathophysiology of autism.