Dai G , Peng C , Liu C , Varnum MD .

EY12836 NEI NIH HHS , R01 EY012836 NEI NIH HHS

	Figure 1. PIP3 or PIP2 potentiates relative cAMP efficacy for homomeric CNGA3 channels. (A) Representative current traces for homomeric CNGA3 channels, elicited by saturating concentrations of cGMP (1 mM, green) or cAMP (10 mM, red), before and after 1 µM PIP3 (diC8-PIP3) application, and after subsequent application of 25 µg/ml poly-lysine (poly-K). Currents were elicited by voltage steps from a holding potential of 0 mV to +80 mV, then to −80 mV and 0 mV (inset). Leak currents in the absence of cyclic nucleotide were subtracted. The arrowhead indicates Imax elicited by cAMP in the presence of PIP3. (B) Time course for the change in maximal cAMP current (in 10 mM cAMP) induced by 1 µM PIP3; also shown is reversal by 25 µg/ml poly-K. Horizontal bars indicate application of respective agents; currents were not recorded during poly-K application. (C) Summary illustrating PIP3 (diC8-PIP3)- or PIP2 (diC8-PIP2)-dependent changes in Imax cAMP/cGMP for CNGA3 and CNGA1 homomeric channels (normalized to control values before treatment). Data are from 10–12 (for PIP3) or 3–4 (for PIP2) independent experiments; *, P < 0.05 relative to before PIPn application (control). The broken horizontal line refers to normalization to the value for Imax cAMP/cGMP of control patches. Error bars indicate mean ± SEM.
	Figure 2. Mutation of critical ligand-discrimination residue (D609) within CNGA3 alters the PIP3-induced increase in relative cAMP efficacy. (A) Diagram illustrating the basic topology of CNGA3 subunits (green), which are comprised of six transmembrane domains, with N- and C-terminal regions located on the intracellular side of the membrane. The light green cylinder represents the Cα helix of the CNBD. The asterisk indicates a critical ligand-discrimination residue, aspartic acid at position 609 (D609) within the CNBD. (B) Representative current traces elicited by 1 mM cGMP (green) or 10 mM cAMP (red) before and after 1 µM PIP3, for CNGA3 D609K and D609M channels. The arrowhead indicates Imax elicited by cGMP in the presence of PIP3. (C) Summary of the effects of 1 µM PIP3 on the current elicited by saturating cAMP or cGMP, for CNGA3 wild-type, D609K, or D609M channels; *, P < 0.05 compared with wild-type channels, n = 4–5. The broken horizontal line refers to a ratio of one, equivalent to no change in the parameter after PIPn application. Error bars indicate mean ± SEM.
	Figure 3. Change in relative cAMP efficacy after PIP3 is dependent on the C-terminal region of CNGA3. (A) Schematic diagram showing sites of truncations and charge neutralizations within the human CNGA3 C-terminal region, and a sequence alignment of this region with orthologous CNGA3 proteins (canine, mouse, bovine, and gallus). Seven conserved lysines and arginines are highlighted in yellow. Bold nucleotides indicate residues in human A3 that were mutated in our study as well as related residues in A3 orthologues. The numbers above the sequence alignment indicate sites for introduced channels. Green highlighting indicates the distal region of the Cα helix. The asterisk indicates D609, as described in Fig. 2. (B) Representative current traces (left), elicited by 1 mM cGMP (green) or 10 mM cAMP (red) before and after 1 µM PIP3, for CNGA3 675X and 635X channels. The right panel summarizes the effects of CNGA3 C-terminal deletions on PIP3-induced increases in cAMP efficacy; *, P < 0.05 compared with wild-type channels, n = 4–9. The arrowhead indicates Imax elicited by cAMP in the presence of PIP3. (C) Representative current traces (left), elicited by 1 mM cGMP (green) or 10 mM cAMP (red) before and after 1 µM PIP3, for A3 C7K/R-A (K624A, K629A, R643A, R646A, K657A, K659A, R661A) and RR-QQ (R643Q, R646Q) channels. The right panel summarizes effects of mutations within the A3 C-terminal region on PIP3-induced increases in cAMP efficacy; *, P < 0.05 compared with wild-type channels, n = 4–6. The broken horizontal lines refer to a ratio of one, equivalent to no change in the parameter after PIPn application. (D) In vitro pull-down assay using PIP3-bound or control agarose beads combined with GST fusion proteins representing the C-terminal region of CNGA3. Input proteins (bottom) and bound proteins (top) were identified by immunoblotting with anti-GST antibodies. A3C, C-terminal region of human CNGA3 from amino acids 612–694; A3C7K/R-A, C-terminal region with seven lysines and arginines neutralized to alanines, as highlighted in A; A3C-635X, C-terminal region of CNGA3 truncated at amino acid 635. Molecular weight markers (in kilodaltons) are shown on the left. Data are representative of four independent experiments. Error bars indicate mean ± SEM.
	Figure 4. N-terminal region of CNGA3 can confer a PIPn-dependent change in apparent cGMP affinity after C-terminal truncation. (A) Subunit diagram and sequence alignment of the N-terminal region of human CNGA3 and rat CNGA2 subunits. The residues highlighted in yellow are conserved arginines in this region of the channel. P99 and A105 of CNGA3, and the corresponding L97 and P103 of CNGA2, are in red. Bold nucleotides indicate residues in human A3 that were mutated in our study as well as related residues in the paralogous rat A2. (B) Representative cGMP concentration–response plots for activation of four different homomeric CNGA3 channels before and after 1 µM PIP3: C-terminal deleted (A3-613X), combined N and C deletions (A3ΔN (51–107), 613X), N-terminal charge neutralizations (R72A, R75A, R81A, R82A, R86A, R101A, R103A) combined with C-terminal truncation (A3-N7R-A, 613X), or P99L, A105P (PA-LP) mutations. Currents were measured at +80 mV and were normalized to the maximum current elicited by a saturating concentration of cGMP. Continuous curves represent fits of the cGMP concentration–response relationship with the Hill equation. Hill parameters of the representative patches were as follows. For A3-613X, K1/2 = 14.7 µM, h = 1.55 before PIP3; K1/2 = 50.9 µM, h = 1.4 after PIP3. For A3 PA-LP, K1/2 = 5.7 µM, h = 1.7 before PIP3; K1/2 = 11.4 µM, h = 1.7 after PIP3. (C) Summary of PIP3-dependent changes in K1/2 cGMP for CNGA3 channels having the specific deletions and/or mutations shown; *, P < 0.05 compared with wild-type A3. (D) N-terminal domain of CNGA3 was expressed as a GST fusion protein and tested for PIP3 binding in vitro by using PIP3-agarose beads. A3N, N-terminal region (amino acids 1–164) of human CNGA3; A3N7R-A, seven arginines were neutralized to alanines within the N-terminal region; A3NΔ51-107, N-terminal region with amino acids 51–107 deleted. Molecular weight markers (in kilodaltons) are shown on the left. Data are representative of four independent experiments. (E) Deletions or charge neutralizations within the N-terminal region of CNGA3, A3 ΔN(2–156) or A3 N7R-A attenuated but did not eliminate the PIP3-induced increase in relative cAMP efficacy (Imax cAMP/cGMP), whereas P99L, L105P (PA-LA) mutations in the N-terminal region eliminated this increase; *, P < 0.05 compared with wild-type A3. The broken horizontal lines refer to a ratio of one, equivalent to no change in the parameter after PIPn application. Error bars indicate mean ± SEM.
	Figure 5. Heteromeric CNGA3+CNGB3 channels are inhibited by PIP3 or PIP2. (A) Representative current traces for heteromeric CNGA3+CNGB3 channels, elicited by subsaturating concentrations of cGMP (5 µM), before (black) and after (red) 1 µM PIP3 or 10 µM PIP2 application for ∼5 min. (B) Representative dose–response relationships for the activation of heteromeric CNGA3+CNGB3 channels by cGMP before and after PIP3 or PIP2 application. The shadings indicate the approximate physiological range of intracellular cGMP levels within vertebrate photoreceptors in the dark. The Hill parameters for each representative patch were: K1/2 cGMP = 16.1 µM, h = 2.05 before PIP3; K1/2 cGMP = 26.5 µM, h = 2.0 after PIP3; K1/2 cGMP = 12.8 µM, h = 1.8 before PIP2; and K1/2 cGMP = 24.5 µM, h = 1.6 after PIP2. (C) Plot of percentage increase in K1/2 cGMP for heteromeric A3+B3 channels at different concentrations of PIP3 (closed squares), PIP2 (closed circles), and natural PIP2 (open circles; n = 4–5 for each PIPn concentration). The PIPn concentration–response relationships were fitted with the Hill equation, and the Hill parameters (K1/2 and h) for each phosphoinositide species were as follows: 0.58 µM and 1.4 for PIP3 (diC8-PIP3), 3.44 µM and 1.5 for PIP2 (diC8-PIP2), and 2.84 µM and 1.4 for natural PIP2. Error bars indicate mean ± SEM.
	Figure 6. Both N- and C-terminal regions of CNGA3 subunits are important for modulation of heteromeric CNGA3+CNGB3 channels by PIP3 or PIP2. (A) Representative cGMP concentration–response plot showing the effect of 10 µM PIP2 on A3+B3 heteromeric channels having N- (N7R-A) and C-terminal (RR-QQ) charge neutralizations within CNGA3. (B) Effects of PIP3 (1 µM) and PIP2 (10 µM) on heteromeric A3+B3 channels having specified mutations in A3 subunits. *, P < 0.05; **, P < 0.001 compared with wild-type A3+B3 for both PIP3 and PIP2. In the pairwise comparisons, statistically significant differences (P < 0.05) were also detected between A3N7R-A+B3 or A3 RR-QQ+B3 versus A3 N7R-A, RR-QQ+B3 channels. (C) Representative cGMP concentration–response relationship for activation of A2ΔN+B3 channels before (black) and after 1 µM PIP3 (red). (D) Percentage change in K1/2 cGMP after PIP3 (1 µM) for various CNG channel subunit compositions. A2ΔN (Brady et al., 2006), A2ΔN+B1, A2ΔN+B3 channels showed no sensitivity to PIP3, whereas PIP3 produced a statistically significant increase in K1/2 cGMP for A1+B3 (n = 4), A2+B3 (n = 3), and A3+B1 (n = 4) channels compared with A2ΔN+B3 or A2ΔN+B1 channels (*, P < 0.05). Error bars indicate mean ± SEM.
	Figure 7. Intersubunit N–C coupling controls phosphoinositide sensitivity of CNGA3 channels. (A) Coexpression of PA-LA subunits with RR-QQ subunits, both of which individually form channels insensitive to 1 µM PIP3 regarding cAMP efficacy, generated channels that were sensitive to PIP3. The Imax cAMP/cGMP (PIP3/control) for coexpression of A3 PA-LA with A3 RR-QQ was 1.67 ± 0.06 (n = 6, P < 0.001). (B) Coexpression of A3 wild type (WT) and A3 N7R-A,613X subunits generated channels that exhibited an increased K1/2 cGMP after 1 µM PIP3 application. Channels formed by A3 WT//A3 N7R-A,613X tandem dimers exhibited enhanced sensitivity to PIP3-induced inhibition of apparent cGMP affinity. Ratio K1/2 cGMP (PIP3/control) was significantly greater for A3//A3 N7R-A,613X dimers (n = 4) compared with channels formed by coexpression of A3 with A3-N7R-A,613X (n = 8; P < 0.05). The broken horizontal lines refer to a ratio of one, equivalent to no change in the parameter after PIPn application. Error bars indicate mean ± SEM.
	Figure 8. Model for tuning phosphoinositide sensitivity of cone CNG channels via intersubunit interactions. Six scenarios here illustrate how proposed N–C interactions between channel subunits may control PIPn regulation. Two regulatory modules are located within the N- and C-terminal regions of CNGA3 subunits, respectively. These PIPn-regulation modules can be silenced (red) or activated (green) due to changes in intersubunit interactions. (i) One component involves the C-terminal region of CNGA3, which is necessary for a PIPn-dependent increase in cAMP efficacy. (ii and v) The other component, manifested as a decrease in apparent cGMP affinity, requires the N-terminal region of CNGA3 and is unmasked either by deletion of the C-terminal region (ii) or by assembly with CNGB3 subunits (v). (iii) PA-LP mutations in CNGA3 also alter N–C coupling, thereby activating the N module and silencing the C module. (iv) The PIPn-regulation competency of channels formed by A3//A3 N7R-A,613X tandem dimers supports an intersubunit N–C interaction. (vi) In addition, PIPn regulation of heteromeric CNGA3+CNGB3 channels depends on N and C regulatory modules in CNGA3.

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