Review
doi: 10.3390/ijms232214143.Retinal Cyclic Nucleotide-Gated Channel Regulation by Calmodulin
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- PMID:36430626
- PMCID: PMC9694239
- DOI: 10.3390/ijms232214143
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Review
Retinal Cyclic Nucleotide-Gated Channel Regulation by Calmodulin
Aritra Bej et al. Int J Mol Sci..
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Abstract
Retinal cyclic nucleotide-gated (CNG) ion channels bind to intracellular cGMP and mediate visual phototransduction in photoreceptor rod and cone cells. Retinal rod CNG channels form hetero-tetramers comprised of three CNGA1 and one CNGB1 protein subunits. Cone CNG channels are similar tetramers consisting of three CNGA3 and one CNGB3 subunits. Calmodulin (CaM) binds to two distinct sites (CaM1: residues 565-587 and CaM2: residues 1120-1147) within the cytosolic domains of rod CNGB1. The binding of Ca2+-bound CaM to CNGB1 promotes the Ca2+-induced desensitization of CNG channels in retinal rods that may be important for photoreceptor light adaptation. Mutations that affect Ca2+-dependent CNG channel function are responsible for inherited forms of blindness. In this review, we propose structural models of the rod CNG channel bound to CaM that suggest how CaM might cause channel desensitization and how dysregulation of the channel may lead to retinal disease.
Keywords: CNGA1; CNGB1; calmodulin; photoreceptor; phototransduction; retina.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Structural overview of CNG channels. (A) Phylogenetic analysis of CNG channel subunits. (B) Cryo-EM structure of CNG channel [14] and ribbon diagrams of CNGA1 (blue) and CNGB1 (red) subunits. The structure of the CaM1 site (asterisks) was not visible in the cryo-EM structures and instead was modeled by AlphaFold [23].
CNG channel function in visual phototransduction. (A) Schematic model of visual excitation regulated by intracellular Ca2+: Light-excited rhodopsin (R*), GTP-bound transducin (Tα-GTP), phosphodiesterase (PDE6), retinal guanylate cyclase (RetGC), guanylate cyclase activating proteins (GCAPs), phosphorylated rhodopsin (R*-P), arrestin (Arr). (B) CNG channel gating by intracellular cGMP in the plasma membrane of rod photoreceptors.
CaM binding sites in rod CNGB1 vs. cone CNGB3. (A) Domain architecture and amino acid sequence of CaM binding sites (CaM1 and CaM2) in CNGB1. Sequence alignment of CaM1 and CaM2 with corresponding residues in CNGA2, creatine kinase (CK), cone CNGB3 and vertebrate homologs of CNGB1. Conserved residues are highlighted in color. (B) NMR structure of the Ca2+-bound CaM N-lobe (light green) bound to CaM1 peptide (red) [53]. (C) Cryo-EM structure of CaM C-lobe (cyan) bound to the D-helix of CNGB1 (red) [13]. (D) NMR structure of the Ca2+-bound CaM C-lobe (dark green) bound to CaM2 peptide (pink) [53].
Two structural models of CNG channel regulation controlled by CaM. (A) Two-site model proposes that CaM binds to two separate sites (CaM1 and CaM2). Adapted from [53]. CNGB1 is highlighted in red. Bound Ca2+ are magenta spheres. The CNG channel at low Ca2+ concentration in light-activated photoreceptors has the Ca2+-bound CaM C-lobe (dark green) bound to CaM2 (light red) and Ca2+-free CaM N-lobe (light green) does not bind to the channel (right panel). The CNG channel at high Ca2+ concentration in the dark-adapted photoreceptor has the Ca2+-bound CaM C-lobe and N-lobe bound to CaM2 and CaM1, respectively (left panel). (B) A one-site model proposes that CaM binds functionally to only one site (CaM2). At high Ca2+ levels, the Ca2+-bound CaM C-lobe binds to CaM2 and is proposed to stabilize the structure of the S6 helix that causes CNGB1 residues (F872, I876 and R880) to point inward to block the channel pore in the desensitized state (see inset). At low Ca2+ levels, the Ca2+-free CaM dissociates from CaM2, which could allow for the channel to switch to a proposed fully open state, as seen in the homomeric CNGA1 [59]. (C) Proposed model for Ca2+-dependent gating of the rod CNG channel. The closed apo state (in the light-activated photoreceptor) has CNGB1 gate residues (L872, I876 and R880) and CNGA1 residues (F389 and V393), each pointing inward to block the ion conduction pathway (left panel). The binding of cGMP causes the formation of a partially open channel (middle panel) in which CNGB1 gate residues are pointing inward to partially block the ion conduction pathway, while CNGA2 residues (F389 and V393) are pointing outward. We propose that the partial open state (middle panel) may represent the desensitized channel state in dark-adapted photoreceptors (high Ca2+ and cGMP). A hypothetical fully open channel (right panel) is proposed to exist at low Ca2+ levels, in which the CNGB1 gate residues are pointing outward to fully unblock the ion conduction pathway. A similar fully open state was observed for the homomeric CNGA1 channel [59] that has each CNGA1 gate residues pointing outward to fully unblock the ion conduction pathway.
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