Retinal rods respond to light with a membrane hyperpolarization produced by a G-protein-mediated signalling cascade that leads to cyclic GMP hydrolysis and the consequent closure of a cGMP-gated channel that is open in darkness. A protein that forms this channel has recently been purified from bovine retina and molecularly cloned, suggesting that the native cGMP-gated channel might be a homo-oligomer. Here we report the cloning of another protein from human retina which has only about 30% overall identity to the rod channel subunit. This protein, immunocytochemically localized to rod outer segments, does not form functional channels by itself. However, when co-expressed with the cloned human rod channel protein, it introduces rapid flickers to the channel openings that are characteristic of the native channel. The hetero-oligomeric channel is also highly sensitive to the blocker L-cis-diltiazem, like the native channel. This new protein thus seems to be another subunit of the native rod channel. The hetero-oligomeric nature of the rod channel means that it is no exception to a common motif shared by other ligand-gated channels.

Although several ion channels have been reported to be directly modulated by calcium-calmodulin, they have not been conclusively shown to bind calmodulin, nor are the modulatory mechanisms understood. Study of the olfactory cyclic nucleotide-activated cation channel, which is modulated by calcium-calmodulin, indicates that calcium-calmodulin directly binds to a specific domain on the amino terminus of the channel. This binding reduces the effective affinity of the channel for cyclic nucleotides, apparently by acting on channel gating, which is tightly coupled to ligand binding. The data reveal a control mechanism that resembles those underlying the regulation of enzymes by calmodulin. The results also point to the amino-terminal part of the olfactory channel as an element for gating, which may have general significance in the operation of ion channels with similar overall structures.