TRPC4 and GIRK channels underlie neuronal coding of firing patterns that reflect G(q/11)–G(i/o) coincidence signals of variable strengths

Transient receptor potential canonical 4 (TRPC4) is a receptor-operated cation channel codependent on both the G(q/11)–phospholipase C signaling pathway and G(i/o) proteins for activation. This makes TRPC4 an excellent coincidence sensor of neurotransmission through G(q/11)- and G(i/o)-coupled receptors. In whole-cell slice recordings of lateral septal neurons, TRPC4 mediates a strong depolarizing plateau that shuts down action potential firing, which may or may not be followed by a hyperpolarization that extends the firing pause to varying durations depending on the strength of G(i/o) stimulation. We show that the depolarizing plateau is codependent on G(q/11)-coupled group I metabotropic glutamate receptors and on G(i/o)-coupled γ-aminobutyric acid type B receptors. The hyperpolarization is mediated by G(i/o) activation of G protein–activated inwardly rectifying K(+) (GIRK) channels. Moreover, the firing patterns, elicited by either electrical stimulation or receptor agonists, encode information about the relative strengths of G(q/11) and G(i/o) inputs in the following fashion. Pure G(q/11) input produces weak depolarization accompanied by firing acceleration, whereas pure G(i/o) input causes hyperpolarization that pauses firing. Although coincident G(q/11)–G(i/o) inputs also pause firing, the pause is preceded by a burst, and both the pause duration and firing recovery patterns reflect the relative strengths of G(q/11) versus G(i/o) inputs. Computer simulations demonstrate that different combinations of TRPC4 and GIRK conductances are sufficient to produce the range of firing patterns observed experimentally. Thus, concurrent neurotransmission through the G(q/11) and G(i/o) pathways is converted to discernible electrical responses by the joint actions of TRPC4 and GIRK for communication to downstream neurons.