Peptides derived from high voltage-gated calcium channel βsubunit reduce blood pressure in rats

초록

The ss subunits of high voltage-gated calcium channels (HGCCs) are essential for optimal channel functions such as channel gating, activation-inactivation kinetics, and trafficking to the membrane. In this study, we report for the first time the potent blood pressure-reducing effects of peptide fragments derived from the ss subunits in anesthetized and non-anesthetized rats. Intravenous administration of 16- mer peptide fragments derived from the interacting regions of the ss 1 [cacb1(344-359)], ss 2 [ cacb2( 392- 407)], ss 3 [cacb3(292-307)], and ss 4 [cacb4( 333348)] subunits with the main a-subunit of HGCC decreased arterial blood pressure in a dose-dependent manner for 5-8 min in anesthetized rats. In contrast, the peptides had no effect on the peak amplitudes of voltage-activated Ca2+ current upon their intracellular application into the acutely isolated trigeminal ganglion neurons. Further, a single mutated peptide of cacb1(344-359)- cacb1(344-359)(K357R)-showed consistent and potent effects and was crippled by a two-amino acid-truncation at the Nterminal or C-terminal end. By conjugating palmitic acid with the second amino acid (lysine) of cacb1(344-359) K-357R (named K2-palm), we extended the blood pressure reduction to several hours without losing potency. This prolonged effect on the arterial blood pressure was also observed in non-anesthetized rats. On the other hand, the intrathecal administration of acetylated and amidated cacb1(344-359) K-357R peptide did not change acute nociceptive responses induced by the intradermal formalin injection in the plantar surface of rat hindpaw. Overall, these findings will be useful for developing antihypertensives.

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