Dexamethasone activates transient receptor potential canonical 4 (TRPC4) channels via Rasd1 small GTPase pathway

Wie, Jinhong; Kim, Jinsung; Ha, Kotdaji; Zhang, Yin Hua; Jeon, Ju Hong; So, Insuk

doi:10.1007/s00424-014-1666-0

Cited by 7 publications

(5 citation statements)

References 31 publications

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“…Indeed, it has been proposed that RASD1 may act to antagonise G protein coupled receptor signaling by altering the pool of heterotrimeric G-proteins available for receptor coupling [ 71 ]. Interestingly, Rasd1 has been reported to selectively activate transient receptor potential channel 4 (TRPC4) in INS-I cells [ 72 ], and altered expression of these channels has been described in vasopressinergic MCNs of the PVN and SON in response to hyperosmotic stress [ 28 , 73 ]. The activation of TRPC4 in neurosecretory cells is known to trigger a robust secretory response [ 74 ], suggesting that Rasd1 may affect the secretion of vasopressin.…”

Section: Discussionmentioning

confidence: 99%

Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation

et al. 2016

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BackgroundRasd1 is a member of the Ras family of monomeric G proteins that was first identified as a dexamethasone inducible gene in the pituitary corticotroph cell line AtT20. Using microarrays we previously identified increased Rasd1 mRNA expression in the rat supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in response to increased plasma osmolality provoked by fluid deprivation and salt loading. RASD1 has been shown to inhibit adenylyl cyclase activity in vitro resulting in the inhibition of the cAMP-PKA-CREB signaling pathway. Therefore, we tested the hypothesis that RASD1 may inhibit cAMP stimulated gene expression in the brain.ResultsWe show that Rasd1 is expressed in vasopressin neurons of the PVN and SON, within which mRNA levels are induced by hyperosmotic cues. Dexamethasone treatment of AtT20 cells decreased forskolin stimulation of c-Fos, Nr4a1 and phosphorylated CREB expression, effects that were mimicked by overexpression of Rasd1, and inhibited by knockdown of Rasd1. These effects were dependent upon isoprenylation, as both farnesyltransferase inhibitor FTI-277 and CAAX box deletion prevented Rasd1 inhibition of cAMP-induced gene expression. Injection of lentiviral vector into rat SON expressing Rasd1 diminished, whereas CAAX mutant increased, cAMP inducible genes in response to osmotic stress.ConclusionsWe have identified two mechanisms of Rasd1 induction in the hypothalamus, one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. We propose that the abundance of RASD1 in vasopressin expressing neurons, based on its inhibitory actions on CREB phosphorylation, is an important mechanism for controlling the transcriptional responses to stressors in both the PVN and SON. These effects likely occur through modulation of cAMP-PKA-CREB signaling pathway in the brain.

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Section: Discussionmentioning

confidence: 99%

Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation

et al. 2016

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“…Small GTPase Rasd1 activates TRPC4β, but not TRPC4α. Glucocorticoids increase Rasd1 in INS-1 cells, and by that way increase the TRPC4 current in these cells [24].…”

Section: Trpc2 Trpc3 Trpc4 Trpc5 and Trpc6mentioning

confidence: 96%

Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells

Islam

2020

Cells

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Insulin secretion from the β-cells of the islets of Langerhans is triggered mainly by nutrients such as glucose, and incretin hormones such as glucagon-like peptide-1 (GLP-1). The mechanisms of the stimulus-secretion coupling involve the participation of the key enzymes that metabolize the nutrients, and numerous ion channels that mediate the electrical activity. Several members of the transient receptor potential (TRP) channels participate in the processes that mediate the electrical activities and Ca2+ oscillations in these cells. Human β-cells express TRPC1, TRPM2, TRPM3, TRPM4, TRPM7, TRPP1, TRPML1, and TRPML3 channels. Some of these channels have been reported to mediate background depolarizing currents, store-operated Ca2+ entry (SOCE), electrical activity, Ca2+ oscillations, gene transcription, cell-death, and insulin secretion in response to stimulation by glucose and GLP1. Different channels of the TRP family are regulated by one or more of the following mechanisms: activation of G protein-coupled receptors, the filling state of the endoplasmic reticulum Ca2+ store, heat, oxidative stress, or some second messengers. This review briefly compiles our current knowledge about the molecular mechanisms of regulations, and functions of the TRP channels in the β-cells, the α-cells, and some insulinoma cell lines.

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“…Related to Ga i protein, Rasd1 and homologs also activated TRPC4 by inducing GTP exchange for Ga i proteins. 75 Interestingly, PTX did not inhibit Rasd1-induced current in the presence of intracellular GTPgS. 75 In the beginning, we thought that Ga i proteins are really essential for the activation of TRPC4.…”

Section: Discussionmentioning

confidence: 99%

“…75 Interestingly, PTX did not inhibit Rasd1-induced current in the presence of intracellular GTPgS. 75 In the beginning, we thought that Ga i proteins are really essential for the activation of TRPC4. However, we could not obtain the clear evidence showing the mutant responding to GTPgS but not Ga i proteins.…”

Section: Discussionmentioning

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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Dexamethasone activates transient receptor potential canonical 4 (TRPC4) channels via Rasd1 small GTPase pathway

Cited by 7 publications

References 31 publications

Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation

Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation

Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells

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

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