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.

研究了丝氨酸在通道内口（域IV S6段的末端）的重要性。它的突变丙氨酸废除了通道通过激活PKA或添加Bay-K8644进入模式2门控的能力。丝氨酸（SER 1517）可以是一个关键的调节位点，该位点与先前研究的Ser 1142在选择性滤波器中的协调，通道对磷酸化和二氢吡啶激动剂的反应。另一方面，在域I的S6螺旋中，甘氨酸至精氨酸的突变会在蒂莫西综合征患者中为SER 439创建共有的phophopophophylation位点，并且具有将Ser 1142突变为ALA的相反作用。这可能是Timothy综合症患者的兴奋性毒性的探索。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，这将是通过防止在SER 1142时进行衰减的promoting模式2门控。