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Functional Role of hCNGB3 in Regulation of Human Cone CNG Channel: Effect of Rod Monochromacy-Associated Mutations in hCNGB3 on Channel Function

¹From the Departments of Ophthalmology, ²Medical Biochemistry, and ³Physiology, Shiga University of Medical Science, Seta, Otsu, Japan; and ⁴Institute of Vision Research, Nagoya, Japan.

PURPOSE. The human cone photoreceptor cyclic nucleotide-gated (CNG) channel comprises - and ß-subunits, which are respectively encoded by hCNGA3 and hCNGB3. The purpose was to examine the functional role of hCNGB3 in modulation of human cone CNG channels and to characterize functional consequences of rod monochromacy-associated mutations in hCNGB3 (S435F and D633G).

METHODS. Macroscopic patch currents were recorded from human embryonic kidney (HEK) 293 cells expressing homomeric (hCNGA3 and hCNGB3) and heteromeric (hCNGA3/hCNGB3, hCNGA3/hCNGB3-S435F, and hCNGA3/hCNGB3-D633G) channels using inside-out patch-clamp technique.

RESULTS. Both hCNGA3 homomeric and hCNGA3/hCNGB3 heteromeric channels were activated by cGMP, with half-maximally activating concentration (K_1/2) of 11.1 ± 1.0 and 26.2 ± 1.9 µM, respectively. The hCNGA3 channels appeared to be more sensitive to inhibition by extracellular Ca²⁺ compared with hCNGA3/hCNGB3 channels, when assessed by the degree of outward rectification. Coexpression of either of rod monochromacy-associated mutants of hCNGB3 with hCNGA3 significantly reduced K_1/2 value for cGMP but little affected the sensitivity to extracellular Ca²⁺, compared with wild-type heteromeric channels. The selectivity of hCNGA3, hCNGA3/hCNGB3, hCNGA3/hCNGB3-S435F, and hCNGA3/hCNGB3-D633G channels for monovalent cations were largely similar. Immunoprecipitation experiments showed association of hCNGA3 subunit with both of wild-type and mutant hCNGB3 subunits.

CONCLUSIONS. The hCNGB3 plays an important modulatory role in the function of human cone CNG channels with respect to cGMP and extracellular Ca²⁺ sensitivities. The rod monochromacy-associated S435F and D633G mutations in hCNGB3 evokes a significant increase in the apparent affinity for cGMP, which should alter cone function and thereby contribute at least partly to pathogenesis of the disease.

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				C. Liu and M. D. Varnum Functional consequences of progressive cone dystrophy-associated mutations in the human cone photoreceptor cyclic nucleotide-gated channel CNGA3 subunit Am J Physiol Cell Physiol, July 1, 2005; 289(1): C187 - C198. [Abstract] [Full Text] [PDF]