The role of the 80-amino acid motif 1572-1651 in the C-terminal tail of α 1 C Ca 2 + channel subunits was studied by comparing properties of the conventional α 1 C , 7 7 channel expressed in HEK-tsA201 cells to three isoforms carrying alterations in this motif. Replacement of amino acids 1572-1651 in α 1 C , 7 7 with 81 non-identical residues leading to α 1 C , 8 6 impaired membrane targeting and cluster formation of the channel. Similar to α 1 C , 8 6 , substitution of its 1572-1598 (α 1 C , 7 7 L ) or 1595-1652 (α 1 C , 7 7 K ) segments into the α 1 C , 7 7 channel yielded single-channel Ba 2 + currents with increased inactivation, reduced open probability and unitary conductance, when compared to the α 1 C , 7 7 channel. Thus, the C-terminal sequence 1572-1651 of the α 1 C subunit is important for membrane targeting, permeation and open probability of L-type Ca 2 + channels.