Transmembrane Signaling through Voltage-gated Ca Channel

通过电压门控 Ca 通道的跨膜信号传导

• 批准号: 7330681
• 负责人: Lutz Birnbaumer
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7330681
• 关键词: Transmembrane; Signaling; through; Voltage; gated

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.

研究了通道内口（结构域IV S6段末端）丝氨酸的重要性。其突变为丙氨酸废除通道进入模式2门控的能力后，通过激活PKA或添加BAY-K8644的刺激。丝氨酸（Ser 1517）可能是一个关键的调节位点，它与先前研究的选择性过滤器中的Ser 1142协调，决定通道对磷酸化和二氢吡啶激动剂的响应。另一方面，结构域I的S6螺旋中的甘氨酸突变为精氨酸，在提摩太综合征患者中产生了Ser 439的共有磷酸化位点，并且具有将Ser 1142突变为Ala的相反效果。这可能是蒂莫西综合征患者兴奋性毒性的解释。模式2门控也可能是与慢性环孢菌素治疗相关的兴奋性毒性的基础，其将通过防止Ser 1142处的去磷酸化来启动模式2门控。