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Modulation of cyclic-nucleotide-gated channels and regulation of vertebrate phototransduction

Richard H. Kramer* and Elena Molokanova

Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA



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  		Fig. 1. The phototransduction cascade. Light causes photoisomerization of rhodopsin, activating the heterotrimeric G-protein transducin. The GTP-bound {alpha}-subunit activates phosphodiesterase (PDE), which degrades cGMP to GMP. The decrease in cGMP concentration leads to closure of cyclic-nucleotide-gated (CNG) channels, resulting in two effects, a decrease in Ca2+ influx and hyperpolarization of the membrane potential. The resulting decrease in intracellular Ca2+ concentration is important for adaptation. Lowered intracellular Ca2+ concentration disinhibits guanylate-cyclase-activating protein (GCAP), leading to activation of guanylate cyclase (GC) and resynthesis of cGMP.

 


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  		Fig. 2. (A) Three-dimensional structure of a cyclic-nucleotide-gated (CNG) channel. Four subunits are arranged to form a common pore. There is a cyclic-nucleotide-binding site on each subunit. (B) Diagram of the primary structure of the {alpha}-subunit. The cylinders indicate hydrophobic segments thought to represent transmembrane domains. The S4 segment is the voltage sensor for voltage-dependent transition in these channels; the region between S5 and S6 is thought to be part of the channel pore (P domain). The cyclic-nucleotide-binding domain is in the C-terminal region of the CNG channel.

 


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  		Fig. 3. Modulation of cyclic-nucleotide-gated (CNG) channels by tyrosine phosphorylation. (A) Changes in amplitude of cGMP-activated current through CNG channels in an excised membrane patch. Currents were elicited by application of cGMP at concentrations of 50, 100, 250 and 2000µmoll-1 and recorded 1 and 10min after patch excision and after a 3min application of 200µmoll-1 ATP. (B) Changes in cGMP-sensitivity of CNG channels after patch excision and subsequent transient application of ATP. (C) Changes in the cyclic-nucleotide-sensitivity (K1/2) exhibited during the first 10min after excision in the presence of serine/threonine and tyrosine protein kinases and phosphatases inhibitors. Values are means + S.E.M. (N=6–16 for different inhibitors).

 


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  		Fig. 4. Schematic model illustrating the activity–dependence of modulation of cyclic-nucleotide-gated (CNG) channels by tyrosine phosphorylation and dephosphorylation. The top and bottom diagrams represent closed and open channels, respectively; the left and right diagrams represent phosphorylated and dephosphorylated channels, respectively. The ovals represent cGMP molecules. The relative thickness of the arrowheads represents changes in the favorability of gating. PTK, protein tyrosine kinase; PTP, protein tyrosine phosphatase.

 


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  		Fig. 5. Insulin-like growth factor I (IGF-I) increases the cyclic-nucleotide-sensitivity of rod cyclic-nucleotide-gated (CNG) channels. (A) An increase in amplitude of the currents activated by application of 8-Br-cGMP (1, 2.5, 10, 25 and 250µmoll-1 from left to right) in excised patches from rods exposed to control saline or to saline containing 10µmoll-1 IGF-I for 10min prior to patch excision. (B) Effects of a 10min pretreatment with 1nmoll-1 to 100µmoll-1 IGF-I (values are means + S.E.M., N=7–25) on the apparent affinity of CNG channels. (C) A suction pipette was used to record the light response of the rods via the inner segment (IS) while permitting continuous superfusion of control or IGF-I-containing solutions on the outer segment (OS). (D) Average rod photoresponse waveforms in response to dim and saturating 10ms light flashes (at time zero) recorded in control saline and 4–6min after the beginning superfusion with 1µmoll-1 IGF-I.

 

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