Selective Gαi Subunits as Novel Direct Activators of Transient Receptor Potential Canonical (TRPC)4 and TRPC5 Channels

Jeon, Jae Pyo; Hong, Chansik; Park, Eun-Jung; Jeon, Ju Hong; Cho, Nam Hyuk; Kim, In Gyu; Choe, Han; Muallem, Shmuel; Kim, Hyun Jin; So, Insuk

doi:10.1074/jbc.m111.326553

Cited by 89 publications

(111 citation statements)

References 44 publications

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“…4A, Right). These characteristics are known to be typical of TRPC channels (26). When cells were pretreated with leptin for 30 min, we observed a significant increase in the double-rectifying nonselective cation currents.…”

Section: Resultssupporting

confidence: 66%

Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells

Park

Ryu²,

Yu³

et al. 2013

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

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103

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Leptin is a pivotal regulator of energy and glucose homeostasis, and defects in leptin signaling result in obesity and diabetes. The ATP-sensitive potassium (K ATP ) channels couple glucose metabolism to insulin secretion in pancreatic β-cells. In this study, we provide evidence that leptin modulates pancreatic β-cell functions by promoting K ATP channel translocation to the plasma membrane via AMP-activated protein kinase (AMPK) signaling. K ATP channels were localized mostly to intracellular compartments of pancreatic β-cells in the fed state and translocated to the plasma membrane in the fasted state. This process was defective in leptin-deficient ob/ob mice, but restored by leptin treatment. We discovered that the molecular mechanism of leptin-induced AMPK activation involves canonical transient receptor potential 4 and calcium/calmodulindependent protein kinase kinase β. AMPK activation was dependent on both leptin and glucose concentrations, so at optimal concentrations of leptin, AMPK was activated sufficiently to induce K ATP channel trafficking and hyperpolarization of pancreatic β-cells in a physiological range of fasting glucose levels. There was a close correlation between phospho-AMPK levels and β-cell membrane potentials, suggesting that AMPK-dependent K ATP channel trafficking is a key mechanism for regulating β-cell membrane potentials. Our results present a signaling pathway whereby leptin regulates glucose homeostasis by modulating β-cell excitability.T he K ATP channel, an inwardly rectifying K + channel that consists of pore-forming Kir6.2 and regulatory sulfonylurea receptor 1 (SUR1) subunits (1), functions as an energy sensor: its gating is regulated mainly by the intracellular concentrations of ATP and ADP. In pancreatic β-cells, K ATP channels are inhibited or activated in response to the rise or fall in blood glucose levels, leading to changes in membrane excitability and insulin secretion (2, 3). Thus, K ATP channel gating has been considered an important mechanism in coupling blood glucose levels to insulin secretion. Recently, trafficking of K ATP channels to the plasma membrane was highlighted as another important mechanism for regulating K ATP channel activity (4-6).AMP-activated protein kinase (AMPK) is a key enzyme regulating energy homeostasis (7). We recently demonstrated that K ATP channels are recruited to the plasma membrane in glucosedeprived conditions via AMPK signaling in pancreatic β-cells (6). Inhibition of AMPK signaling significantly reduces K ATP currents, even after complete wash-out of intracellular ATP (6). Given these results, we proposed a model that recruitment of K ATP channels to the plasma membrane via AMPK signaling is crucial for K ATP channel activation in low-glucose conditions. However, the physiological relevance of this model remains unclear because pancreatic β-cells had to be incubated in media containing less than 3 mM glucose to recruit a sufficient number of K ATP channels to the plasma membrane (6). We thus hypothesized that there should be an e...

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Section: Resultssupporting

confidence: 66%

Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells

Park

Ryu²,

Yu³

et al. 2013

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

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103

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“…(21,(24)(25)(26)(27)(28)32). To determine if IP 3 Rs are involved in TRPC4 activation, we applied the IP 3 R inhibitor heparin (3 mg/mL) by intracellular dialysis and found that most cells failed to respond to DAMGO and subsequent application of CCh (Fig. 3 A-C).…”

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

confidence: 99%

“…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)(3)(4).…”

mentioning

confidence: 99%

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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“…1,2,13 . Related to Ga i protein, Rasd1 and homologs also activated TRPC4 by inducing GTP exchange for Ga i proteins.…”

Section: Discussionmentioning

confidence: 99%

“…1,13 Also, Rasd1 is functionally classified as a guanine nucleotide exchange factor (GEF) for Ga i proteins 46 and facilitates guanosine diphosphate (GDP) to GTP exchange of Ga i proteins and triggers it to be functionally active until intrinsic GTPase activity of Ga i protein turns off the signal by hydrolyzing GTP to GDP. Therefore, since the function of Rasd1 as a GEF of Ga i may resemble the activators of Ga i proteins, we expressed Rasd1 and mTRPC4b in HEK293 cells and detected the effect of Rasd1 on the activity of mTRPC4b.…”

Section: Trpc4 Channelsmentioning

confidence: 99%

The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels

et al. 2015

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#These authors contributed equally to this work TRPC4 is important regulators of electrical excitability in gastrointestinal myocytes, pancreatic b-cells and neurons. Much is known regarding the assembly and function of these channels including TRPC1 as a homotetramer or a heteromultimer and the roles that their interacting proteins play in controlling these events. Further, they are one of the best-studied targets of G protein-coupled receptors and growth factors in general and Ga i/o and Ga q protein coupled receptor or epidermal growth factor and leptin in particular. However, our understanding of the roles of small G proteins and leptin on TRPC4 channels is still rudimentary. We discuss potential roles for Rasd1 small G protein and leptin in channel activation in addition to their known role in cellular signaling.

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Selective Gαi Subunits as Novel Direct Activators of Transient Receptor Potential Canonical (TRPC)4 and TRPC5 Channels

Cited by 89 publications

References 44 publications

Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells

Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells

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

The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels

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Selective Gαi Subunits as Novel Direct Activators of Transient Receptor Potential Canonical (TRPC)4 and TRPC5 Channels

Cited by 89 publications

References 44 publications

Leptin promotes K ATP channel trafficking by AMPK signaling in pancreatic β-cells

Leptin promotes K ATP channel trafficking by AMPK signaling in pancreatic β-cells

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

The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels

Contact Info

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Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells

Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells

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