PT - JOURNAL ARTICLE AU - L. Lacinová AU - R. H. An AU - J. Xia AU - H. Ito AU - N. Klugbauer AU - D. Triggle AU - F. Hofmann AU - R. S. Kass TI - Distinctions in the Molecular Determinants of Charged and Neutral Dihydropyridine Block of L-Type Calcium Channels DP - 1999 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1472--1479 VI - 289 IP - 3 4099 - http://jpet.aspetjournals.org/content/289/3/1472.short 4100 - http://jpet.aspetjournals.org/content/289/3/1472.full SO - J Pharmacol Exp Ther1999 Jun 01; 289 AB - We investigated block of the α1Cb subunit of L-type calcium channels by dihydropyridines (DHPs) in which a permanently charged or neutral head group was linked to the active DHP moiety by a spacer chain containing ten methylene (−CH2) groups. We compared the sensitivity of channel modulation by the charged (DHPch) and neutral (DHPn) forms to specific α1Cb mutations in domains IIIS5, IIIS6, and IVS6, which had previously been shown to reduce channel modulation by the neutral DHP (+)-isradipine. The effects of these mutations were studied on channel block recorded from polarized (−80 mV) and depolarized (−40 mV) holding potentials (HPs). We found that channel block by DHPn was markedly reduced at both HPs by each mutation studied. In contrast, channel block by DHPch was only modestly reduced by mutations in IIIS6 and IVS6 for block from either −40 mV or −80 mV. Replacement of IIIS5 Thr1061 by Tyr, which abolished block by DHPn in an HP-independent manner, had little effect on channel block by DHPch recorded from −40 mV. However, this mutation markedly reduced DHPch block of currents recorded from a −80 mV HP. Inhibition of current by DHPch was not markedly use-dependent, in contrast with block by verapamil, another charged calcium channel blocker. These results suggest that the presence of a permanently charged head group restricts the access of the attached DHP moiety to a subset of interaction residues on the α1C subunit in a voltage-dependent manner. Furthermore, these restricted interactions confer distinct functional properties upon the charged DHP molecules. The American Society for Pharmacology and Experimental Therapeutics