The Journal of General Physiology
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Published 30 July 2001. doi:10.1085/jgp.118.2.183
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© The Rockefeller University Press, 0022-1295/2001/8/183/ $5.00
The Journal of General Physiology, Volume 118, Number 2, August 1, 2001 183-192

Original Article

Molecular Regions Controlling the Activity of CNG Channels

Holger Möttiga, Jana Kuscha, Thomas Zimmera, Annette Schollea, and Klaus Benndorfa
a Institut für Physiologie, Abteilung Herz-Kreislauf-Physiologie, Friedrich-Schiller-Universität Jena, 07740 Jena, Germany

Correspondence to: Klaus Benndorf, Friedrich-Schiller-Universität Jena, Institut für Physiologie, Herz-Kreislauf-Physiologie, D-07740 Jena, Germany. Fax:49-3641-933202 E-mail:kben{at}mti-n.uni-jena.de.

The {alpha} subunits of CNG channels of retinal photoreceptors (rod) and olfactory neurons (olf) are proteins that consist of a cytoplasmic NH2 terminus, a transmembrane core region (including the segments S1–S6), and a cytoplasmic COOH terminus. The COOH terminus contains a cyclic nucleotide monophosphate binding domain NBD) that is linked by the C-linker (CL) to the core region. The binding of cyclic nucleotides to the NBD promotes channel opening by an allosteric mechanism. We examined why the sensitivity to cGMP is 22 times higher in olf than in rod by constructing chimeric channels and determining the [cGMP] causing half maximum channel activity (EC50). The characteristic difference in the EC50 value between rod and olf was introduced by the NH2 terminus and the core-CL region, whereas the NBD showed a paradoxical effect. The difference of the free energy difference {Delta}({Delta}G) was determined for each of these three regions with all possible combinations of the other two regions. For rod regions with respect to corresponding olf regions, the open channel conformation was destabilized by the NH2 terminus ({Delta}({Delta}G) = -1.0 to -2.0 RT) and the core-CL region ({Delta}({Delta}G) = -2.0 to -2.9 RT), whereas it was stabilized by the NBD ({Delta}({Delta}G) = 0.3 to 1.1 RT). The NH2 terminus deletion mutants of rod and olf differed by {Delta}({Delta}G) of only 0.9 RT, whereas the wild-type channels differed by the much larger value of 3.1 RT. The results show that in rod and olf, the NH2 terminus, the core-CL region, and the NBD differ by characteristic {Delta}({Delta}G) values that do not depend on the specific composition of the other two regions and that the NH2 terminus generates the main portion of {Delta}({Delta}G) between the wild-type channels.

Key Words: ion channel, ligand, cyclic nucleotide, gating


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