ArticleProceedings of the National Academy of Sciences of the United States of America2016
Critical roles of Gi/o proteins and phospholipase C-δ1 in the activation of receptor-operated TRPC4 channels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 72 citations in OpenAlex.
- The nonexcitable smooth muscle: remodeling the smooth muscle ion transport toolkit in disease.Physiological reviews · 2026Review
- TRPC Channels as Mediators of Hypoxia-Induced Pulmonary Hypertension in Obstructive Sleep Apnea.International journal of molecular sciences · 2026Review
- Physiological functions and pharmacological targeting of transient receptor potential channels.Pharmacological reviews · 2025Review
- TRPC4/5 inhibitors: Phase I results and proof of concept studies.European archives of psychiatry and clinical neuroscience · 2025Review
- TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel.Nature structural & molecular biology · 2025Article
- Molecular Organization of Autonomic, Respiratory, and Spinally-Projecting Neurons in the Mouse Ventrolateral Medulla.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Role of TRP channels in carcinogenesis and metastasis: Pathophysiology and regulation by non-coding RNAs.Non-coding RNA research · 2024Review
- Unique responses of the fixed stoichiometric TRPC1-TRPC5 concatemer to G proteins.Frontiers in physiology · 2024Article
- Direct modulation of TRPC ion channels by Gα proteins.Frontiers in physiology · 2024Review
- Negative self-regulation of transient receptor potential canonical 4 by the specific interaction with phospholipase C-δ1.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2023Article
- TRPC4 and GIRK channels underlie neuronal coding of firing patterns that reflect GProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Role of Calcium Homeostasis in Modulating EMT in Cancer.Biomedicines · 2021Review
- TRP channels in health and disease at a glance.Journal of cell science · 2021Article
- Blockade of TRPC Channels Limits Cholinergic-Driven Hyperexcitability and Seizure Susceptibility After Traumatic Brain Injury.Frontiers in neuroscience · 2021Article
- TRPC4 as a coincident detector of GCurrent opinion in physiology · 2020Article
- Review
- N-benzhydryl quinuclidine compounds are a potent and Src kinase-independent inhibitor of NALCN channels.British journal of pharmacology · 2020Article
- Intracellular acidification facilitates receptor-operated TRPC4 activation through PLCδ1 in a CaThe Journal of physiology · 2020Article
- TRPC channels: Structure, function, regulation and recent advances in small molecular probes.Pharmacology & therapeutics · 2020Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Transient Receptor Potential Canonical (TRPC) proteins form nonselective cation channels commonly known to be activated downstream from receptors that signal through phospholipase C (PLC). Although TRPC3/C6/C7 can be directly activated by diacylglycerols produced by PLC breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2), the mechanism by which the PLC pathway activates TRPC4/C5 remains unclear. We show here that TRPC4 activation requires coincident stimulation of Gi/o subgroup of G proteins and PLCδ, with a preference for PLCδ1 over PLCδ3, but not necessarily the PLCβ pathway commonly thought to be involved in receptor-operated TRPC activation. In HEK293 cells coexpressing TRPC4 and Gi/o-coupled µ opioid receptor, µ agonist elicited currents biphasically, with an initial slow phase preceding a rapidly developing phase. The currents were dependent on intracellular Ca(2+) and PIP2. Reducing PIP2 through phosphatases abolished the biphasic kinetics and increased the probability of channel activation by weak Gi/o stimulation. In both HEK293 cells heterologously expressing TRPC4 and renal carcinoma-derived A-498 cells endogenously expressing TRPC4, channel activation was inhibited by knocking down PLCδ1 levels and almost completely eliminated by a dominant-negative PLCδ1 mutant and a constitutively active RhoA mutant. Conversely, the slow phase of Gi/o-mediated TRPC4 activation was diminished by inhibiting RhoA or enhancing PLCδ function. Our data reveal an integrative mechanism of TRPC4 on detection of coincident Gi/o, Ca(2+), and PLC signaling, which is further modulated by the small GTPase RhoA. This mechanism is not shared with the closely related TRPC5, implicating unique roles of TRPC4 in signal integration in brain and other systems.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.