title: Molecular determinants of the modulation of cyclic nucleotide-activated channels by calmodulin.
abstract: The action of calmodulin (CaM) on target proteins is important for a variety of cellular functions. We demonstrate here, however, that the presence of a CaM-binding site on a protein does not necessarily imply a functional effect. The alpha-subunit of the cGMP-gated cation channel of human retinal cones has a CaM-binding site on its cytoplasmic N-terminal region, but the homomeric channel that it forms is not functionally modulated by CaM. Mutational analysis based on comparison to the highly homologous olfactory cyclic nucleotide-gated channel alpha-subunit, which does form a CaM-modulated channel, indicates that residues downstream of the CaM-binding domain on these channels are also important for CaM to have an effect. These findings suggest that a CaM-binding site and complementary structural features in a protein probably evolve independently, and an effect caused by CaM occurs only in the presence of both elements. More generally, the same may be true for other recognized binding sites on proteins for modulators or activators, so that a demonstrated physical interaction does not necessarily imply functional consequence.
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Grunwald
authors.forename: H
authors.initials: H
authors.lastname: Zhong
authors.forename: J
authors.initials: J
authors.lastname: Lai
authors.forename: K W
authors.initials: KW
authors.lastname: Yau
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002147:Calmodulin / Q000378:metabolism / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D054815:Cyclic Nucleotide-Gated Cation Channels; D044385:GTP-Binding Protein alpha Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D051381:Rats; D017386:Sequence Homology, Amino Acid
chemical_list: D002147:Calmodulin; D054815:Cyclic Nucleotide-Gated Cation Channels; D044385:GTP-Binding Protein alpha Subunits; D007473:Ion Channels; C084618:olfactory G protein subunit alpha olf; D020962:Heterotrimeric GTP-Binding Proteins; D006152:Cyclic GMP