Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations

Schwerin, Stefan; Westphal, Catharina; Klug, Claudia; Schneider, Gerhard; Kreuzer, Matthias; Haseneder, Rainer; Kratzer, Stephan

doi:10.3390/ijms24010519

Open AccessArticle

Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations

by

Stefan Schwerin

,

Catharina Westphal

,

Claudia Klug

,

Gerhard Schneider

,

Matthias Kreuzer

^*,

Rainer Haseneder

and

Stephan Kratzer

Department of Anesthesiology and Intensive Care Medicine, Klinikum Rechts der Isar, Technical University of Munich School of Medicine, 81675 Munich, Germany

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2023, 24(1), 519; https://doi.org/10.3390/ijms24010519

Submission received: 24 November 2022 / Revised: 19 December 2022 / Accepted: 20 December 2022 / Published: 28 December 2022

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Germany)

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Abstract

Dexmedetomidine is a selective α₂-adrenoceptor agonist and appears to disinhibit endogenous sleep-promoting pathways, as well as to attenuate noradrenergic excitation. Recent evidence suggests that dexmedetomidine might also directly inhibit hyperpolarization-activated cyclic-nucleotide gated (HCN) channels. We analyzed the effects of dexmedetomidine on native HCN channel function in thalamocortical relay neurons of the ventrobasal complex of the thalamus from mice, performing whole-cell patch-clamp recordings. Over a clinically relevant range of concentrations (1–10 µM), the effects of dexmedetomidine were modest. At a concentration of 10 µM, dexmedetomidine significantly reduced maximal I_h amplitude (relative reduction: 0.86 [0.78–0.91], n = 10, and p = 0.021), yet changes to the half-maximal activation potential V_1/2 occurred exclusively in the presence of the very high concentration of 100 µM (−4,7 [−7.5–−4.0] mV, n = 10, and p = 0.009). Coincidentally, only the very high concentration of 100 µM induced a significant deceleration of the fast component of the HCN activation time course (τ_fast: +135.1 [+64.7–+151.3] ms, n = 10, and p = 0.002). With the exception of significantly increasing the membrane input resistance (starting at 10 µM), dexmedetomidine did not affect biophysical membrane properties and HCN channel-mediated parameters of neuronal excitability. Hence, the sedative qualities of dexmedetomidine and its effect on the thalamocortical network are not decisively shaped by direct inhibition of HCN channel function.

Keywords: dexmedetomidine; hcn channel; thalamus; thalamocortical relay neuron; patch-clamp; anesthesia

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MDPI and ACS Style

Schwerin, S.; Westphal, C.; Klug, C.; Schneider, G.; Kreuzer, M.; Haseneder, R.; Kratzer, S. Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations. Int. J. Mol. Sci. 2023, 24, 519. https://doi.org/10.3390/ijms24010519

AMA Style

Schwerin S, Westphal C, Klug C, Schneider G, Kreuzer M, Haseneder R, Kratzer S. Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations. International Journal of Molecular Sciences. 2023; 24(1):519. https://doi.org/10.3390/ijms24010519

Chicago/Turabian Style

Schwerin, Stefan, Catharina Westphal, Claudia Klug, Gerhard Schneider, Matthias Kreuzer, Rainer Haseneder, and Stephan Kratzer. 2023. "Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations" International Journal of Molecular Sciences 24, no. 1: 519. https://doi.org/10.3390/ijms24010519

APA Style

Schwerin, S., Westphal, C., Klug, C., Schneider, G., Kreuzer, M., Haseneder, R., & Kratzer, S. (2023). Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations. International Journal of Molecular Sciences, 24(1), 519. https://doi.org/10.3390/ijms24010519

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Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations

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