Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030.
Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Proc Natl Acad Sci U S A. 2022 May 17;119(20):e2120870119. doi: 10.1073/pnas.2120870119. Epub 2022 May 11.
Transient receptor potential canonical 4 (TRPC4) is a receptor-operated cation channel codependent on both the Gq/11–phospholipase C signaling pathway and Gi/o proteins for activation. This makes TRPC4 an excellent coincidence sensor of neurotransmission through Gq/11- and Gi/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 Gi/o stimulation. We show that the depolarizing plateau is codependent on Gq/11-coupled group I metabotropic glutamate receptors and on Gi/o-coupled γ-aminobutyric acid type B receptors. The hyperpolarization is mediated by Gi/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 Gq/11 and Gi/o inputs in the following fashion. Pure Gq/11 input produces weak depolarization accompanied by firing acceleration, whereas pure Gi/o input causes hyperpolarization that pauses firing. Although coincident Gq/11–Gi/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 Gq/11 versus Gi/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 Gq/11 and Gi/o pathways is converted to discernible electrical responses by the joint actions of TRPC4 and GIRK for communication to downstream neurons.
瞬时受体电位经典型 4（TRPC4）是一种受体操纵的阳离子通道，其激活既依赖于 Gq/11-磷脂酶 C 信号通路，也依赖于 Gi/o 蛋白。这使得 TRPC4 成为神经递质传递的理想巧合传感器，通过 Gq/11 和 Gi/o 偶联受体进行传递。在横向隔神经元的全细胞膜片记录中，TRPC4 介导强烈的去极化平台，从而关闭动作电位的发放，该平台随后可能会或可能不会发生超极化，从而根据 Gi/o 刺激的强度将发放暂停延长到不同的时间。我们表明，去极化平台既依赖于 Gq/11 偶联的 I 型代谢型谷氨酸受体，也依赖于 Gi/o 偶联的γ-氨基丁酸 B 型受体。超极化是由 Gi/o 激活 G 蛋白激活内向整流钾（GIRK）通道介导的。此外，无论是电刺激还是受体激动剂引起的放电模式，都以以下方式对 Gq/11 和 Gi/o 输入的相对强度进行编码信息。纯 Gq/11 输入产生弱去极化，伴随着放电加速，而纯 Gi/o 输入引起超极化，从而暂停放电。尽管同时存在 Gq/11-Gi/o 输入也会暂停放电，但暂停之前会出现爆发，暂停持续时间和放电恢复模式反映了 Gq/11 与 Gi/o 输入的相对强度。计算机模拟表明，不同组合的 TRPC4 和 GIRK 电导足以产生实验中观察到的放电模式范围。因此，通过 Gq/11 和 Gi/o 途径的并发神经递质传递通过 TRPC4 和 GIRK 的联合作用转化为可识别的电响应，以便与下游神经元进行通信。
