Figure 6. Schematics of role of GGG and 9* in modulating β-adrenergic regulation of Ca_V1.2.

(A) Ribbon representation of the published two Ca_V1.1 conformations determined by cryo-EM ⁴⁰ with GGG, AID and exon 9* mutations/insertions in the I-II loop. Left: 5GJV, Right: 5GJW. (B) Proposed models of β−adrenergic regulation of WT, GGG-α_1C and 9*-α_1C channels. Basal state (left) and after β-adrenergic agonist (stimulated, right). β-agonist-induced activation of adenylyl cyclase (AC) leads to activation of PKA. PKA phosphorylates several residues on Rad, causing dissociationof Rad from the Ca_V1.2 complex and therefore increased Ca²⁺ influx. Under basal conditions, the GGG-α_1C channels have reduced basal open probability and no response to β-adrenergic stimulation. In contrast to the polyglycine substitution, modifying the I-II loop by introduction of the 9* splice variant increased the basal open probability, yet the stimulatory response to β−adrenergic agonists was preserved.