Figure 3: Molecular determinants of Cav1.2 inactivation. Comparison of the wild-type Cav1.2 (A) with the same channel deprived of CDI (B) and SI (C) determinants. The five horizontal panels show (a) arrangement of critical determinants of inactivation. ADSI is composed of conserved hydrophobic amino acids in a -2 position of S6 segments in repeats II, III, and IV (yellow circles: Ala, Val, and Ile, resp.) as well as Ser residue in -1 position of IS6 (cyan circle). The CaM-binding domain (CBD) of the α 1C C-tail is shown by a red rounded rectangle. A β subunit (green) binds to the α-interaction domain in the linker between repeats I and II, and, in a Ca2+-dependent manner, to the IQ-region of the α 1C subunit C-tail ([45], not shown). The distal structure of β 2 (β 2CED, blue ball) binds to the CBD [46]. (b) Evidence of coimmunoprecipitation of the indicated subunits. (c) Normalized traces of (black) and (red), and (d) voltage dependence of (red) and time constant of FI ( , black) are presented to illustrate CDI in (A) and lack of CDI in (B) and (C). (e) Link between CDI and differential β-subunit modulation (DβM) of Cav1.2. (A) Differential modulation of the inactivation by β 1a (black trace) and β 2a (green trace) in the WT Cav1.2. Disruption of CBD (α 1C,86) eliminates CDI and SI targeted by CDI and DβM (B). Mutation of ADSI (α 1C,IS-IV) removed CDI and fully inhibited SI so that the channel remains conducting for the duration of the depolarization stimulus (C).