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<p>Temperature strongly influences neuronal excitability and voltage-gated ion channel function. Ca<sub>v</sub>3.2&#xa0;T-type calcium channels are highly expressed in dorsal root ganglion and trigeminal ganglion neurons, where they contribute to nociceptive signaling, cold hypersensitivity, and neuropathic pain. However, how temperature influences Ca<sub>v</sub>3.2 function during repetitive neuronal activity remains incompletely understood. Here, we investigated the effects of temperature on Ca<sub>v</sub>3.2 gating and calcium influx using whole-cell voltage-clamp recordings performed at 37&#xa0;°C, 22&#xa0;°C, and 13&#xa0;°C. Cooling markedly reduced macroscopic current amplitude under conventional voltage-step protocols while profoundly slowing activation, inactivation, deactivation, and recovery from inactivation kinetics. In contrast, steady-state voltage dependence was comparatively less affected, revealing highly non-uniform temperature sensitivity across distinct gating transitions. During trains of action-potential-like waveforms delivered at 10–100&#xa0;Hz, increasing stimulation frequency progressively inverted the temperature dependence of Ca<sub>v</sub>3.2-mediated calcium influx. Although cooling reduced peak current amplitude, it promoted sustained channel activity and enhanced cumulative calcium influx during high-frequency stimulation. This functional inversion resulted from disproportionate slowing of channel gating kinetics, particularly inactivation and deactivation. A kinetically slowed Ca<sub>v</sub>3.2 variant (V416R) reproduced key low-temperature kinetic features and markedly attenuated this inversion. Together, these findings identify a previously unrecognized temperature-dependent functional inversion of Ca<sub>v</sub>3.2 channels during repetitive activity with potentially important pathophysiological implications.</p>

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Temperature-dependent functional inversion of Cav3.2 channels during repetitive activity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Kacper Pawlak,
  • Petr Daněk,
  • Bohumila Jurkovičová-Tarabová,
  • Norbert Weiss

摘要

Temperature strongly influences neuronal excitability and voltage-gated ion channel function. Cav3.2 T-type calcium channels are highly expressed in dorsal root ganglion and trigeminal ganglion neurons, where they contribute to nociceptive signaling, cold hypersensitivity, and neuropathic pain. However, how temperature influences Cav3.2 function during repetitive neuronal activity remains incompletely understood. Here, we investigated the effects of temperature on Cav3.2 gating and calcium influx using whole-cell voltage-clamp recordings performed at 37 °C, 22 °C, and 13 °C. Cooling markedly reduced macroscopic current amplitude under conventional voltage-step protocols while profoundly slowing activation, inactivation, deactivation, and recovery from inactivation kinetics. In contrast, steady-state voltage dependence was comparatively less affected, revealing highly non-uniform temperature sensitivity across distinct gating transitions. During trains of action-potential-like waveforms delivered at 10–100 Hz, increasing stimulation frequency progressively inverted the temperature dependence of Cav3.2-mediated calcium influx. Although cooling reduced peak current amplitude, it promoted sustained channel activity and enhanced cumulative calcium influx during high-frequency stimulation. This functional inversion resulted from disproportionate slowing of channel gating kinetics, particularly inactivation and deactivation. A kinetically slowed Cav3.2 variant (V416R) reproduced key low-temperature kinetic features and markedly attenuated this inversion. Together, these findings identify a previously unrecognized temperature-dependent functional inversion of Cav3.2 channels during repetitive activity with potentially important pathophysiological implications.