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Ca 2 1 -sensitive inactivation of L-type Ca 2 1 channels depends on multiple cytoplasmic amino acid sequences of the a 1C subunit

Ca 2 1 -dependent inactivation of Ca 2 1 currents is a physiological phenomenon widely associated with L-type Ca 2 1 channels. Although the pore-forming a 1C subunit of the channel is the target for Ca 2 1 binding, the amino acid sequences involved in the binding and y or in the coordination of Ca 2 1 -dependent inactivation are still unclear. Based on previous experiments, we have prepared truncation mutants of a human a 1C subunit by systematically deleting an EF-hand motif and sequences in a segment of 80 amino acids in the carboxyl-terminal tail. We found that the rate as well as the Ca 2 1 dependence of inactivation of currents through these mutated channels were very different. We have identified three amino acid sequences, the presence of which is important for Ca 2 1 -dependent inactivation: ( i ) a putative Ca 2 1 -binding EF-hand motif, ( ii ) two hydrophilic residues (asparagine and glutamic acid) 77–78 amino acids downstream of the EF-hand motif, and ( iii ) a putative IQ calmodulin binding motif. We suggest that Ca 2 1 -dependent inactivation is a cooperative process involving several amino acid sequences in cytoplasmic segments of the a 1C subunit. The voltage-gated L-type Ca 2 1 channel is an essential part of signal transduction systems in many cell types. The channel is a heteromeric protein complex that occurs in several subunit combinations (1, 2). The cardiac type Ca 2 1 channel consists of the pore-forming