CAMP AND G-PROTEIN REGULATION OF CARDIAC SODIUM CHANNELS

CAMP 和 G 蛋白对心脏钠离子通道的调节

• 批准号: 2445261
• 负责人: ERWIN F SHIBATA
• 金额: $ 21.27万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2445261
• 关键词: G protein; cyclic AMP; electrophysiology; enzyme inhibitors; forskolin; heart cell; laboratory rabbit; phosphorylation; protein kinase A; second messengers; sodium channel; synthetic peptide; voltage gated channel

DESCRIPTION (adapted from the applicant's abstract): This proposal is an extension of observations to pursue the basic mechanisms by which cAMP- dependent phosphorylation and the direct action of Gsa modulate INa in rabbit cardiac myocytes. First, the mechanisms by which cAMP- dependent phosphorylation modulates INa will be determined. Studying INa in cell- attached and inside-out membrane patches, the effects of forskolin, cell permeable cAMP analogs, and the catalytic subunit of PKA on the number of active channels (N), the probability of channel opening (Po), and the unitary current amplitude (i) of the sodium channel will be determined. The first latency and channel reopening, m(t), distributions and the analysis of runs will also be performed. The effect of protein phosphatases on cardiac INa will also be studied. Second, the mechanisms by which the direct effects of Gsa on INa will be determined. The cAMP-dependent pathways will be investigated using the PKA inhibitor peptide (PKI) and the voltage-dependence of the Gsa effects on INa will be studied. The effect of Gsa on INa activation and inactivation on N, Po, and i of single sodium channels will also be examined. The applicant also plans to delineate the INa-activating domain(s) of Gsa by studying the effects of synthetic peptides with sequences homologous to various segments of native Gsa. Finally, the applicant proposes that there are important interactions between the direct Gsa and the cAMP-mediated pathways in the modulation of INa. He will study the effects of sodium channel phosphorylation and dephosphorylation on the modulation of INa by the direct effects of Gsa.

描述（改编自申请人的摘要）：该提案是 扩大观察范围，以探讨基本机制， cAMP依赖性磷酸化和Gsa调节INa的直接作用 在兔心肌细胞中。首先，cAMP- 依赖性磷酸化调节INa。学习INa 在细胞贴附和由内而外的膜贴片中， 毛喉素、细胞可渗透性cAMP类似物和PKA的催化亚基 在活动信道的数量（N）上，信道打开的概率 (Po)，钠通道的单位电流幅度（i）将 被确定。第一等待时间和信道重新打开m（t）， 还将进行分布和运行分析。的 还将研究蛋白磷酸酶对心脏INa的影响。 第二，Gsa对INa的直接影响将 被确定。cAMP依赖性途径将使用 PKA抑制肽（PKI）与Gsa的电压依赖性 将研究对INa的影响。Gsa对INa激活的影响， 对单钠通道的N、Po和i的失活也将被 考察申请人还计划描绘INa激活 通过研究合成肽对Gsa结构域的影响， 与天然Gsa的各种区段同源的序列。 最后 本申请人提出，在这些物质之间存在重要的相互作用， 直接Gsa和cAMP介导的途径调节INa。他 将研究钠通道磷酸化的影响， 通过Gsa的直接作用，去磷酸化对INa的调节。

项目成果

Molecular determinants of intracellular pH modulation of human Kv1.4 N-type inactivation.

人 Kv1.4 N 型失活的细胞内 pH 调节的分子决定因素。

• DOI: 10.1124/mol.62.1.127
• 发表时间: 2002
• 期刊: Molecular pharmacology
• 影响因子: 3.6
• 作者: Padanilam,BenzyJ;Lu,Tong;Hoshi,Toshinori;Padanilam,BeenaA;Shibata,ErwinF;Lee,Hon-Chi
• 通讯作者: Lee,Hon-Chi

Palytoxin disrupts cardiac excitation-contraction coupling through interactions with P-type ion pumps.

海藻毒素通过与 P 型离子泵的相互作用破坏心脏兴奋-收缩耦合。

• DOI: 10.1152/ajpcell.00541.2003
• 发表时间: 2004
• 期刊: American journal of physiology. Cell physiology
• 作者: Kockskämper,Jens;Ahmmed,GiasU;Zima,AlekseyV;Sheehan,KatherineA;Glitsch,HelfriedG;Blatter,LotharA
• 通讯作者: Blatter,LotharA