Capsazepine (CPZ) was recognized as a synthetic inhibitor of capsaicin activation of TRPV1 channel. TRPV1 has been demonstrated to be widely distributed in endocrine or neuroendocrine cells, and different types of central neurons. However, whether and how this compound might produce any perturbations on varying types of ionic currents, other than block of capsaicin-induced TRPV1 or activation of epithelial Na+ current, remain largely unclear. In this study, we aimed to clarify the effect of CPZ on hyperpolarization-activated cationic current (Ih, or HCN-encoded current) and voltage-gated Na+ current (INa) in pituitary GH3 cells. By use of whole-cell patch-clamp recordings, the CPZ application caused a concentration-dependent inhibition of Ih amplitude or slowing in activation time course of the current with the measured IC50 or KD value of 3.1 or 3.16 μM, respectively. The steady-state activation curve of Ih during the exposure to 3 μM CPZ was shifted toward more hyperpolarized potential by approximately 20 mV; however, no change in the gating charge of the current was noticed. In this work, a modified Markovian model designed for Ih was implemented to evaluate the plausible modifications of CPZ on the hysteresis of the current; and the model was well suited to predict CPZ-mediated decrease in hysteretic strength of Ih. The INa identified in GH3 cells was also suppressed by CPZ, despite the activation or inactivation time course of the current was changed. Moreover, under cell-attached current measurements, cell exposure to CPZ resulted in a reduction of spontaneous firing. Collectively, finding the current observations suggest that CPZ-perturbed inhibition of Ih or INa appears to be direct and independent of its action on vanilloid receptor(s); hence, such actions would be a yet unidentified but important ionic mechanism underlying perturbed intrinsic membrane excitability in the in-vivo endocrine or neuroendocrine cells, or neurons.
Experimental motivation: The objective is to examine the effect of capsazepine on hyperpolarization-activated inward current (Ih).
Model Type: Channel/Receptor
Region(s) or Organism(s):
Cell Type(s):
Currents: I h
Receptors:
Transmitters:
Model Concept(s): Ion Channel Kinetics
Simulation Environment: XPPAUT
Implementer(s): Wu, Sheng-Nan [snwu at mail.ncku.edu.tw]; Tsai, Chung-Hung
References:
Wong SL, Shih CL, Cho HY, Wu SN. (2024). Effective suppression of Ih and INa caused by capsazepine, known to be a blocker of TRPV1 receptor. Brain research. [PubMed]