Substitution of a Single Residue in Stichodactyla helianthus Peptide, ShK-Dap22, Reveals a Novel Pharmacological Profile

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• 作者：Richard E. Middleton ; Manuel Sanchez ; Ana-Rosa Linde ; Randal M. Bugianesi ; Ge Dai ; John P. Felix ; Sam L. Koprak ; Mary Jo Staruch ; Marc Bruguera ; Rachael Cox ; Amrita Ghosh ; Jeremy Hwang ; Simmonette Jon
• 刊名：Biochemistry
• 出版年：2003
• 出版时间：November 25, 2003
• 年：2003
• 卷：42
• 期：46
• 页码：13698 - 13707
• 全文大小：153K
• 年卷期：v.42,no.46(November 25, 2003)
• ISSN：1520-4995

文摘

ShK, a peptide isolated from Stichodactyla helianthus venom, blocks the voltage-gated potassiumchannels, K_v1.1 and K_v1.3, with similar high affinity. ShK-Dap²², a synthetic derivative in which adiaminopropionic acid residue has been substituted at position Lys²², has been reported to be a selectiveK_v1.3 inhibitor and to block this channel with equivalent potency as ShK [Kalman et al. (1998) J. Biol.Chem. 273, 32697-32707]. In this study, a large body of evidence is presented which indicates that thepotencies of wild-type ShK peptide for both K_v1.3 and K_v1.1 channels have been previously underestimated.Therefore, the affinity of ShK-Dap²² for both channels appears to be ca. 10²-10⁴-fold weaker than ShK.ShK-Dap²² does display ca. 20-fold selectivity for human K_v1.3 vs K_v1.1 when measured by the whole-cell voltage clamp method but not in equilibrium binding assays. ShK-Dap²² has low affinity for K_v1.2channels, but heteromultimeric K_v1.1-K_v1.2 channels form a receptor with ca. 200-fold higher affinity forShK-Dap²² than K_v1.1 homomultimers. In fact, K_v1.1-K_v1.2 channels bind ShK-Dap²² with only ca. 10-fold less potency than ShK and reveal a novel pharmacology not predicted from the homomultimers ofK_v1.1 or K_v1.2. The concentrations of ShK-Dap²² needed to inhibit human T cell activation were ca.10³-fold higher than those of ShK, in good correlation with the relative affinities of these peptides forinhibiting K_v1.3 channels. All of these data, taken together, suggest that ShK-Dap²² will not have thesame in vivo immunosuppressant efficacy of other K_v1.3 blockers, such as margatoxin or ShK. Moreover,ShK-Dap²² may have undesired side effects due to its interaction with heteromultimeric K_v1.1-K_v1.2channels, such as those present in brain and/or peripheral tissues.