Kang Hana, Kim Jinhyeong, Park Christine Haewon, Jeong Byeongseok, So Insuk
Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Physiology, University of California, San Francisco, San Francisco, CA, United States.
Front Physiol. 2024 Feb 7;15:1362987. doi: 10.3389/fphys.2024.1362987. eCollection 2024.
GPCR-G protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of internal visceral organs. The muscarinic receptor-operated cationic channel is important in GPCR-G protein signal transduction as it decreases heart rate and increases GI rhythm frequency. In the SA node of the heart, acetylcholine binds to the M2 receptor and the released Gβγ activates GIRK (I(K,ACh)) channel, inducing a negative chronotropic action. In gastric smooth muscle, there are two muscarinic acetylcholine receptor (mAChR) subtypes, M2 and M3. M2 receptor activates the muscarinic receptor-operated nonselective cationic current (mIcat, NSCC(ACh)) and induces positive chronotropic effect. Meanwhile, M3 receptor induces hydrolysis of PIP and releases DAG and IP. This IP increases intracellular Ca and then leads to contraction of GI smooth muscles. The activation of mIcat is inhibited by anti-G protein antibodies in GI smooth muscle, indicating the involvement of Gα protein in the activation of mIcat. TRPC4 channel is a molecular candidate for mIcat and can be directly activated by constitutively active Gα proteins. TRPC4 and TRPC5 belong to the same subfamily and both are activated by G proteins. Initial studies suggested that the binding sites for G protein exist at the rib helix or the CIRB domain of TRPC4/5 channels. However, recent cryo-EM structure showed that IYY amino acids at ARD of TRPC5 binds with G protein. Considering the expression of TRPC4/5 in the brain, the direct G protein activation on TRPC4/5 is important in terms of neurophysiology. TRPC4/5 channels are also suggested as a coincidence detector for G and G pathway as G pathway increases intracellular Ca and the increased Ca facilitates the activation of TRPC4/5 channels. More complicated situation would occur when GIRK, KCNQ2/3 (I) and TRPC4/5 channels are co-activated by stimulation of muscarinic receptors at the acetylcholine-releasing nerve terminals. This review highlights the effects of GPCR-G protein pathway, including dopamine, μ-opioid, serotonin, glutamate, GABA, on various oragns, and it emphasizes the importance of considering TRPC4/5 channels as crucial players in the field of neuroscience.
GPCR-G蛋白通路在生理条件下参与迷走神经毒蕈碱通路的调节，并与内脏器官的调节密切相关。毒蕈碱受体操纵的阳离子通道在GPCR-G蛋白信号转导中很重要，因为它能降低心率并增加胃肠节律频率。在心脏的窦房结中，乙酰胆碱与M2受体结合，释放的Gβγ激活GIRK（I(K,ACh)）通道，产生负性变时作用。在胃平滑肌中，有两种毒蕈碱型乙酰胆碱受体（mAChR）亚型，即M2和M3。M2受体激活毒蕈碱受体操纵的非选择性阳离子电流（mIcat，NSCC(ACh)）并诱导正性变时效应。同时，M3受体诱导磷脂酰肌醇二磷酸（PIP）水解，释放二酰甘油（DAG）和肌醇三磷酸（IP）。这种IP增加细胞内钙离子浓度，进而导致胃肠平滑肌收缩。在胃肠平滑肌中，抗G蛋白抗体可抑制mIcat的激活，表明Gα蛋白参与了mIcat的激活。瞬时受体电位通道4（TRPC4）是mIcat的一个分子候选者，可被组成型活性Gα蛋白直接激活。TRPC4和TRPC5属于同一亚家族，均由G蛋白激活。初步研究表明，G蛋白的结合位点存在于TRPC4/5通道的核糖体螺旋或CIRB结构域。然而，最近的冷冻电镜结构显示，TRPC5的ARD结构域中的IYY氨基酸与G蛋白结合。考虑到TRPC4/5在大脑中的表达，G蛋白对TRPC4/5的直接激活在神经生理学方面很重要。TRPC4/5通道也被认为是G和G通路的巧合探测器，因为G通路增加细胞内钙离子浓度，而增加的钙离子促进TRPC4/5通道的激活。当GIRK、钾通道Q2/3（I）和TRPC4/5通道在乙酰胆碱释放神经末梢被毒蕈碱受体刺激共同激活时，会出现更复杂的情况。本综述强调了GPCR-G蛋白通路，包括多巴胺、μ-阿片类、5-羟色胺、谷氨酸、γ-氨基丁酸，对各种器官的影响，并强调了将TRPC4/5通道视为神经科学领域关键参与者的重要性。
