Temperature dependence of HCN channel kinetics: A systematic comparison across mammalian isoforms and species.

Overview

1. Blue Brain Project, Ecole Polytechnique Fédérale de Lausanne (EPFL), Geneva, Switzerland
2. Laboratory of Neural Microcircuitry, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

Abstract

Hyperpolarization‐activated, cyclic nucleotide‐gated (HCN) channels are important regulators of cardiac pacemaking and neuronal excitability, yet their temperature dependence has not been compared systematically across mammalian isoforms and species in standardized experimental conditions. Here, we performed a standardized electrophysiological characterization of mouse, rat and human HCN isoforms using stable CHO cell lines and automated patch‐clamp recordings across multiple temperatures and pharmacological conditions. Among the four isoforms, HCN3 did not generate detectable currents when expressed as a homomeric channel in the conditions tested, suggesting that additional factors might be required for functional activity. Comparative analysis of the remaining isoforms revealed a conserved kinetic hierarchy, with HCN1 exhibiting the fastest activation kinetics, HCN2 intermediate kinetics and HCN4 the slowest, and temperature accelerated channel gating across isoforms. Canonical modulation by cAMP and ZD7288 further showed that key regulatory features of HCN channels could be quantified reproducibly in identical experimental conditions. Together, these results provide a standardized comparative framework for interpreting HCN channel behaviour across physiological temperatures and species and establish a public reference dataset for future experimental and computational studies.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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The paper's code and data availability statement is in the Data section.

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Data

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Data availability statement

The raw electrophysiological recordings and analysis code are available via Channelpedia (https://www.channelpedia.net/). Any additional data or materials required to reanalyse the findings of this study are available from the corresponding author upon reasonable request. This study did not generate new, unique reagents.

Reproduced under the paper's license (CC BY), from the paper cited above.

Electrophysiological data availability for HCN channels

All electrophysiological recordings generated in this study have been made publicly available through the Channelpedia (Ranjan et al., 2011) platform to facilitate data sharing, reproducibility and further analysis by the scientific community. The dataset includes raw electrophysiological traces, processed kinetic parameters and associated experimental metadata for the HCN channel experiments reported in this study.

The recordings are provided in a standardized HDF5‐based file format (The HDF Group, 2025), enabling efficient storage and cross‐platform accessibility of large electrophysiological datasets. Through the Channelpedia interface, users can browse individual recordings, visualize electrophysiological responses and download complete datasets corresponding to specific channels, species, temperatures or experimental conditions.

To facilitate programmatic access and downstream data analysis further, we provide dedicated application programming interfaces (APIs) for both MATLAB and Python. These APIs allow users to retrieve and analyse electrophysiological recordings directly from Channelpedia within commonly used scientific computing environments. Example scripts and documentation are available to guide users in accessing and processing the data.

Together, these resources provide an open and standardized framework for accessing large‐scale electrophysiological datasets, enabling researchers to reproduce the analyses presented in this study and to perform independent investigations of HCN channel kinetics.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, pages, dates, 6 authors, 8 keywords, 1 funder, 28 references, 1 RRID.

Cite

This paper

Ranjan, R., Logette, E., Herzog, M., Buchillier, V., Scantamburlo, E., & Markram, H. (2026). Temperature dependence of HCN channel kinetics: A systematic comparison across mammalian isoforms and species. Experimental physiology, 10.1113/EP093939. https://doi.org/10.1113/ep093939

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