Calmodulin supports both inactivation and facilitation of L-type calcium channels

L-type Ca2+ channels support Ca2+ entry into cells, which triggers cardiac contraction(1), controls hormone secretion from endocrine cells(2) and init iates transcriptional events that support learning and memory(3). These cha nnels are examples of molecular signal-transduction units that regulate the mselves through their own activity. Among the many types of voltage-gated C a2+ channel, L-type Ca2+ channels particularly display inactivation and fac ilitation, both of which are closely linked to the earlier entry of Ca2+ io ns(4-10). Both forms of autoregulation have a significant impact on the amo unt of Ca2+ that enters the cell during repetitive activity, with major con sequences downstream. Despite extensive biophysical analysis(9), the molecu lar basis of autoregulation remains unclear, although a putative Ca2+-bindi ng EF-hand motif(11,12) and a nearby consensus calmodulin-binding isoleucin e-glutamine ('IQ') motif(13,14) in the carboxy terminus of the alpha(1C) ch annel subunit have been implicated(12,14-16). Here we show that calmodulin is a critical Ca2+ sensor for both inactivation and facilitation, and that the nature of the modulatory effect depends on residues within the IQ motif important for calmodulin binding. Replacement of the native isoleucine by alanine removed Ca2+-dependent inactivation and unmasked a strong facilitat ion; conversion of the same residue to glutamate eliminated both forms of a utoregulation. These results indicate that the same calmodulin molecule may act as a Ca2+ sensor for both positive and negative modulation.