Histamine depolarizes rat intracardiac ganglion neurons through the activation of TRPC non-selective cation channels.

The cardiac plexus, which contains parasympathetic ganglia, plays an important role in regulating cardiac function. Histamine is known to excite intracardiac ganglion neurons, but the underlying mechanism is obscure. In the present study, therefore, the effect of histamine on rat intracardiac ganglion neurons was investigated using perforated patch-clamp recordings. Histamine depolarized acutely isolated neurons with a half-maximal effective concentration of 4.5 μM. This depolarization was markedly inhibited by the H receptor antagonist triprolidine and mimicked by the H receptor agonist 2-pyridylethylamine, thus implicating histamine H receptors. Consistently, reverse transcription-PCR (RT-PCR) and Western blot analyses confirmed H receptor expression in the intracardiac ganglia. Under voltage-clamp conditions, histamine evoked an inward current that was potentiated by extracellular Ca removal and attenuated by extracellular Na replacement with N-methyl-D-glucamine. This implicated the involvement of non-selective cation channels, which given the link between H receptors and G-protein-phospholipase C signalling, were suspected to be transient receptor potential canonical (TRPC) channels. This was confirmed by the marked inhibition of the inward current through the pharmacological disruption of either G signalling or intracellular Ca release and by the application of the TRPC blockers Pyr3, Gd and ML204. Consistently, RT-PCR analysis revealed the expression of several TRPC subtypes in the intracardiac ganglia. Whilst histamine was also separately found to inhibit the M-current, the histamine-induced depolarization was only significantly inhibited by the TRPC blockers Gd and ML204, and not by the M-current blocker XE991. These results suggest that TRPC channels serve as the predominant mediator of neuronal excitation by histamine.