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Thermodynamics of Activation Gating in Olfactory-Type Cyclic Nucleotide-Gated (CNGA2) Channels

Vasilica Nache ^*, Jana Kusch ^*, Christoph Biskup ^*, Eckhard Schulz , Thomas Zimmer ^*, Volker Hagen  and Klaus Benndorf ^*

^* Institut für Physiologie II, Friedrich-Schiller-Universität Jena, Jena, Germany; Fachhochschule Schmalkalden, Fachbereich Elektrotechnik, Schmalkalden, Germany; and Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany

Correspondence: Address reprint requests to Klaus Benndorf, E-mail: klaus.benndorf{at}mti.uni-jena.de.

Olfactory-type cyclic nucleotide-gated (CNG) ion channels open by the binding of cyclic nucleotides to a binding domain in the C-terminus. Employing the Eyring rate theory, we performed a thermodynamic analysis of the activation gating in homotetrameric CNGA2 channels. Lowering the temperature shifted the concentration-response relationship to lower concentrations, resulting in a decrease of both the enthalpy H and entropy S upon channel opening, suggesting that the order of an open CNGA2 channel plus its environment is higher than that of the closed channel. Activation time courses induced by cGMP concentration jumps were used to study thermodynamics of the transition state. The activation enthalpies H were positive at all cGMP concentrations. In contrast, the activation entropy S was positive at low cGMP concentrations and became then negative at increasing cGMP concentrations. The enthalpic and entropic parts of the activation energies approximately balance each other at all cGMP concentrations, leaving the free enthalpy of activation in the range between 19 and 21 kcal/mol. We conclude that channel activation proceeds through different pathways at different cGMP concentrations. Compared to the unliganded channel, low cGMP concentrations generate a transitional state of lower order whereas high cGMP concentrations generate a transitional state of higher order.