Transmembrane Signaling through Voltage-gated Ca Channel

研究了通道内口(结构域IV S6段末端)丝氨酸的重要性。它的丙氨酸突变使通道在激活PKA或加入Bay-K8644的刺激下进入模式2门控的能力丧失。丝氨酸(Ser1517)可能是一个关键的调控位点，与先前在选择性过滤器中研究的Ser1142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Timothy综合征患者中，结构域I的S6螺旋上的甘氨酸到精氨酸的突变创建了Ser 439的一个共识磷酸化位点，并具有将Ser 1142突变为Ala的相反效果。这可能是Timothy综合征患者兴奋中毒的原因。模式2门控也可能是慢性环孢素治疗相关兴奋毒性的基础，这将通过阻止Ser1142上的去磷化来促进模式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.