The Timothy syndrome mutations G402S and G406R abolish inactivation of Ca(V)1.2 
and cause multiorgan dysfunction and lethal arrhythmias. To gain insights into 
the consequences of the G402S mutation on structure and function of the channel, 
we systematically mutated the corresponding Gly-432 of the rabbit channel and 
applied homology modeling. All mutations of Gly-432 (G432A/M/N/V/W) diminished 
channel inactivation. Homology modeling revealed that Gly-432 forms part of a 
highly conserved structure motif (G/A/G/A) of small residues in homologous 
positions of all four domains (Gly-432 (IS6), Ala-780 (IIS6), Gly-1193 (IIIS6), 
Ala-1503 (IVS6)). Corresponding mutations in domains II, III, and IV induced, in 
contrast, parallel shifts of activation and inactivation curves indicating a 
preserved coupling between both processes. Disruption between coupling of 
activation and inactivation was specific for mutations of Gly-432 in domain I. 
Mutations of Gly-432 removed inactivation irrespective of the changes in 
activation. In all four domains residues G/A/G/A are in close contact with 
larger bulky amino acids from neighboring S6 helices. These interactions 
apparently provide adhesion points, thereby tightly sealing the activation gate 
of Ca(V)1.2 in the closed state. Such a structural hypothesis is supported by 
changes in activation gating induced by mutations of the G/A/G/A residues. The 
structural implications for Ca(V)1.2 activation and inactivation gating are 
discussed.