Cnga4

CNGA4 is a cyclic nucleotide-gated (CNG) channel subunit. CNG channels are members of an ion channel superfamily that includes voltage-gated channels, and all share a common six transmembrane domain topology. CNG channels exhibit some common structural motifs found in most other members of this channel superfamily, including a fourth membrane-spanning segment (S4) reminiscent of a voltage sensor motif, even though CNG channels exhibit only minimal voltage dependence. CNGA4, like other CNG channel subunits, contains a cyclic nucleotide-binding domain (CNBD) in its intracellular C-terminus. CNGA4 is expressed largely in olfactory receptor neurons (ORNs) of the main olfactory epithelium, although expression has also been reported in the vomeronasal organ and some regions of the central nervous system (CNS). It is a constituent, along with the CNGA2 and CNGB1b subunits, of the heterotetrameric olfactory CNG channel, a non-selective cation channel that plays a central role in cAMP-mediated odor transduction. This channel has a subunit composition of one CNGA4, one CNGB1b and two CNGA2 subunits. In contrast to the rod photoreceptor CNG channels, which are largely insensitive to cAMP, the olfactory CNG channel is highly sensitive to both cAMP and cGMP. CNGA4 cannot form functional homomeric channels that are activated by cyclic nucleotides; therefore, the cyclic nucleotide sensitivity and selectivity of this subunit alone is unknown. The olfactory CNG channel is not only a critical component of the odor-dependent activation mechanisms in ORNs, but is also a principal target of a Ca²⁺-dependent negative feedback mechanism that underlies odor adaptation. Calmodulin molecules associated with an unconventional apo-calmodulin-binding site in the C-linker region of CNGA4 are an important part of the Ca²⁺-dependent negative feedback mechanism that underlies the rapid adaptation of the olfactory CNG channel by decreasing channel affinity for cyclic nucleotides.