Transmembrane Signaling through Voltage-gated Ca Channel

研究了通道内口（S6结构域末端）丝氨酸的重要性。它的丙氨酸突变取消了通道在激活PKA或添加BAY-K8644的刺激下进入模式2门控的能力。丝氨酸（Ser 1517）可能是一个关键的调控位点，它与先前研究的选择性过滤器中的Ser 1142协同决定通道对磷酸化和二氢吡啶激动剂的响应。另一方面，在I结构域S6螺旋上的甘氨酸突变为精氨酸，在蒂莫西综合征患者中为Ser 439创造了一个一致的磷酸化位点，而将Ser 1142突变为Ala具有相反的效果。这可能是对蒂莫西综合征患者兴奋性中毒的解释。模式2门控也可能是与慢性环孢素治疗相关的兴奋性毒性的基础，它可能通过阻止Ser 1142的去磷酸化来促进模式2门控。

The importance of a serine at the inner mouth of the channel (end of domain IV S6 segment) was studied. Its mutation to alanine abrogated the ability of the channel to enter into mode 2 gating upon stimulation by activation of PKA or addition of BAY-K8644. The serine (Ser 1517) may be a key regulatory site that determines, in coordination with the previously studied Ser 1142 in the selectivity filter, the responsivenes of the channel to phosphorylation and the dihydropyridine agonist. On the other hand, mutation of a Glycine to to Arginine in the S6 helix of domain I, creates a consensus phophorylation site for Ser 439 in Timothy's syndrome patients and has the opposite effect of mutating Ser 1142 to Ala. This may be the explanation for the excitotoxisity in Timothy's syndrome patients. Mode 2 gating may also be the basis for excitotoxicities associated with chronic cyclosporin treatment, which would be prmoting mode 2 gating by preventing de-phophorylation at Ser 1142.