Receptor-operated cation channels formed by TRPC4 and TRPC5

Plant, Tim; Schaefer, Michael

doi:10.1007/s00210-005-1055-5

Cited by 70 publications

(53 citation statements)

References 81 publications

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“…Subsequent addition of μ agonist DAMGO (1 μM) caused robust currents, with current-voltage (I-V) relationships typical of TRPC4/C5, such as a negative slope between 10 and 40 mV and outward rectification at more positive potentials (2-4, 14-16). The near-linear I-V relation at negative potentials indicates very strong channel activation (14,15). Consistent with μOR being G i/o -coupled, the currents were abolished by treatment with pertussis toxin (PTX) (SI Appendix, Fig.…”

Section: Trpc4 Activation Requires Coincident G I/o Stimulation and Plcmentioning

confidence: 75%

Critical roles of G_i/oproteins and phospholipase C-δ1 in the activation of receptor-operated TRPC4 channels

Thakur

Tian

Jeon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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 (PIP 2 ), the mechanism by which the PLC pathway activates TRPC4/C5 remains unclear. We show here that TRPC4 activation requires coincident stimulation of G i/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 G i/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 PIP 2 . Reducing PIP 2 through phosphatases abolished the biphasic kinetics and increased the probability of channel activation by weak G i/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 G i/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 G i/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.Canonical TRPs (TRPC1-7) are the most homologous to the prototypical Drosophila TRP and are believed to be activated downstream of phospholipase C (PLC) (1). In both heterologous and native systems, stimulating PLCβ via the G q/11 subgroup of G proteins is commonly used to activate TRPC channels. Recent studies, however, also suggest a role for G i/o subgroup of G proteins in the activation of TRPC4/C5 (2-4).TRPC4 is implicated in the regulation of microvascular permeability (5), renal cancer proliferation (6, 7), neurotransmitter release (8), intestinal contraction and motility (9), neurite extension (10), epileptiform burst firing, and seizure-induced neurodegeneration (11). The channel mediates Na + and Ca 2+ influx, causing membrane depolarization and intracellular Ca 2+ concentration ([Ca 2+ ] i ) elevation, which in turn alter cell function (12). Although advances have been made in demonstrating TRPC4 channel activation under G i/o and/or PLC stimulation, as well as its dependence on [Ca 2+ ] i , a precise description of signaling events underlying the mechanism of TRPC4 activation remains elusive.Here, we distinguished the contributions of G q/11 and G i/o pathways to TRPC4 activation and uncovered a strict codependence on G i/o and PLC pathways. We focuse...

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Section: Trpc4 Activation Requires Coincident G I/o Stimulation and Plcmentioning

confidence: 75%

Critical roles of G_i/oproteins and phospholipase C-δ1 in the activation of receptor-operated TRPC4 channels

Thakur

Tian

Jeon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…These proteins are activated by intracellular signals generated upon hormonal stimulation (Zufall 2005;Dietrich et al 2005;Plant and Schaefer 2005). The TRPV family is formed by proteins related to the vanilloid receptor 1 or capsaicin receptor 1 (Clapham et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Function and pharmacology of TRPM cation channels

Harteneck

2005

Naunyn-Schmiedeberg's Arch Pharmacol

145

126

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The physiological function and cellular role of some members of the TRPM family are poorly understood and still mysterious. Melastatin, the founding member of the TRPM group, is the most prominent example of the mysteries involved in understanding TRP channel function. Melastatin or TRPM1 was first cloned in 1998 and since then it has been suggested that it functions as a tumor suppressor protein in melanocytes. On the other hand, TRPM8 and TRPA1 have been described as cold receptors, TRPM4 and TRPM5 as calcium-activated nonselective cation channels, TRPM6 and TRPM7 as magnesium-permeable and magnesium-modulated cation channels, TRPM2 as an ADPribose-activated channel of macrophages, and TRPM3 as a hypo-osmolarity-and sphingosine-activated channel. There are many unsolved questions and many studies have to be performed to understand the overall function of the TRPM family. In addition to electrophysiological recordings and biochemical characterization, the use of compounds modulating TRPM channel function has often been helpful to study TRPM channels in a cellular context. Therefore, the review will summarize the known functions, activation mechanisms, and pharmacological modulations of the TRPM channels.

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“…Characteristic IV relationships were identified for many homo-and heteromeric ion channels, including members of the transient receptor potential (TRP) channel family (30,31). However, in the case of GlyRs, detailed information about isoform-specific characteristics of IV relationships is not available, especially for ␣2-and ␣3-containing GlyRs that are involved in neuropathic pain, temporal lobe epilepsy, and autism spectrum disorder (3)(4)(5)(6).…”

mentioning

confidence: 99%

Electrophysiological Signature of Homomeric and Heteromeric Glycine Receptor Channels

Raltschev

Hetsch

Winkelmann

et al. 2016

Journal of Biological Chemistry

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Glycine receptors are chloride-permeable, ligand-gated ion channels and contribute to the inhibition of neuronal firing in the central nervous system or to facilitation of neurotransmitter release if expressed at presynaptic sites. Recent structure-function studies have provided detailed insights into the mechanisms of channel gating, desensitization, and ion permeation. However, most of the work has focused only on comparing a few isoforms, and among studies, different cellular expression systems were used. Here, we performed a series of experiments using recombinantly expressed homomeric and heteromeric glycine receptor channels, including their splice variants, in the same cellular expression system to investigate and compare their electrophysiological properties. Our data show that the current-voltage relationships of homomeric channels formed by the ␣2 or ␣3 subunits change upon receptor desensitization from a linear to an inwardly rectifying shape, in contrast to their heteromeric counterparts. The results demonstrate that inward rectification depends on a single amino acid (Ala 254 ) at the inner pore mouth of the channels and is closely linked to chloride permeation. We also show that the current-voltage relationships of glycine-evoked currents in primary hippocampal neurons are inwardly rectifying upon desensitization. Thus, the alanine residue Ala 254 determines voltage-dependent rectification upon receptor desensitization and reveals a physio-molecular signature of homomeric glycine receptor channels, which provides unprecedented opportunities for the identification of these channels at the single cell level.

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Receptor-operated cation channels formed by TRPC4 and TRPC5

Cited by 70 publications

References 81 publications

Critical roles of G_i/oproteins and phospholipase C-δ1 in the activation of receptor-operated TRPC4 channels

Critical roles of G_i/oproteins and phospholipase C-δ1 in the activation of receptor-operated TRPC4 channels

Function and pharmacology of TRPM cation channels

Electrophysiological Signature of Homomeric and Heteromeric Glycine Receptor Channels

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Receptor-operated cation channels formed by TRPC4 and TRPC5

Cited by 70 publications

References 81 publications

Critical roles of Gi/oproteins and phospholipase C-δ1 in the activation of receptor-operated TRPC4 channels

Critical roles of Gi/oproteins and phospholipase C-δ1 in the activation of receptor-operated TRPC4 channels

Function and pharmacology of TRPM cation channels

Electrophysiological Signature of Homomeric and Heteromeric Glycine Receptor Channels

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Product

Resources

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Critical roles of G_i/oproteins and phospholipase C-δ1 in the activation of receptor-operated TRPC4 channels

Critical roles of G_i/oproteins and phospholipase C-δ1 in the activation of receptor-operated TRPC4 channels