A molecular determinant of nickel inhibition in Cav3.2 T-type calcium channels

doi:10.1074/jbc.M510197200

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Papers In Press, published online ahead of print December 23, 2005
J. Biol. Chem, 10.1074/jbc.M510197200
Submitted on September 16, 2005
Revised on December 22, 2005
Accepted on December 23, 2005

A molecular determinant of nickel inhibition in Ca_v3.2 T-type calcium channels

Ho-Won Kang, Jin-Yong Park, Seong-Woo Jeong, Jin-Ah Kim, Hyung-Jo Moon, Edward Perez-Reyes, and Jung-Ha Lee

Life Science, Sogang University, Seoul 121-742

Corresponding Author: jhleem{at}sogang.ac.kr

Molecular cloning studies have revealed that heterogeneity of T-type Ca²⁺ currents in native tissues arises from the three isoforms of Ca_v3 channels: Ca_v3.1, Ca_v3.2, and Ca_v3.3. From pharmacological analysis of the recombinant T-type channels, low concentrations (<50 µM) of nickel were found to selectively block the Ca_v3.2 over the other isoforms. To date, however, the structural element(s) responsible for the nickel block on the Ca_v3.2 T-type Ca²⁺ channel remain unknown. Thus, we constructed chimeric channels between the nickel-sensitive Ca_v3.2 and the nickel-insensitive Ca_v3.1 to restrict the region interacting with nickel. Systematic assaying of serial chimeras suggests that the region preceding domain I S4 of the Ca_v3.2 contributes to nickel block. Point mutations of potential nickel-interacting sites revealed that H191Q in the S3-S4 loop of domain I significantly attenuated the nickel block of Ca_v3.2, mimicking the nickel insensitive blocking potency of Ca_v3.1. These findings indicate that H191 in the S3-S4 loop is a critical residue conferring nickel block to the Ca_v3.2, and reveals a novel role for the S3-S4 loop to control ion permeation through T-type Ca²⁺ channels.

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