Mechanism of calcium/calmodulin inhibition of rod cyclic nucleotide-gated channels

Rod cyclic nucleotide-gated (CNG) channels are heterotetramers comprised of both CNGA1 and CNGB1 subunits. Calcium/calmodulin (Ca2+/CaM) binds to a site in the N-terminal region of CNGB1 subunits and inhibits the opening conformational change in CNGA1/CNGB1 channels. Here, we show that polypeptides derived from an N-terminal region of CNGB1 form a specific interaction with polypeptides derived from a C-terminal region of CNGA1 that is distal to the cyclic nucleotide-binding domain. Deletion of the Ca2+/CaM-binding site from the N-terminal region of CNGB1 eliminated both Ca2+/CaM modulation of the channel and the intersubunit interaction. Furthermore, the interaction was disrupted by the presence of Ca2+/CaM. These results suggest that Ca2+/CaM-dependent inhibition of rod channels is caused by the direct binding of Ca2+/CaM to a site in the N-terminal region in CNGB1, which disrupts the interaction between this region and a distal C-terminal region of CNGA1. The mechanism underlying Ca2+/XaM modulation of rod channels is distinct from that in olfactory (CNGA2) CNG channels.