The β-cell GHSR and downstream cAMP/TRPM2 signaling account for insulinostatic and glycemic effects of ghrelin

Kurashina, Tomoyuki; Dezaki, Katsuya; Yoshida, Masashi; Rita, Rauza Sukma; K, Ito; Taguchi, Masanobu; Miura, Rina; Tominaga, Makoto; Ishibashi, Shun; Kakei, Masafumi; Yada, Toshihiko

doi:10.1038/srep14041

Cited by 51 publications

(52 citation statements)

References 54 publications

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“…This unique signal coupling to the cAMP level in the cell antagonizes the glucose stimulation of insulin secretion that activates EPAC2/TRPM2 as has been described above and potentiates the triggering pathway in GSIS [36,59]. This hypothesis can be confirmed because ghrelin antagonizes GSIS by counteracting cAMP production by glucose [60] (see Fig. 3, P-3 and P-4).…”

Section: Trpm2 Channels As a Glp-1 Mechanism Potentiating Gsissupporting

confidence: 66%

Glucose and GTP-binding protein-coupled receptor cooperatively regulate transient receptor potential-channels to stimulate insulin secretion [Review]

et al. 2016

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Abstract. In pancreatic β-cells, glucose-induced closure of the ATP-sensitive K + (KATP) channel is an initial process triggering glucose-stimulated insulin secretion (GSIS). This KATP-channel dependent pathway has been believed to be a central mechanism for GSIS. However, since the resting membrane potential of cells is determined by the balance of the net result of current amplitudes in outward and inward directions, it must be taken into consideration that not only KATP channel inhibition but also inward current via the basal opening of non-selective cation channels (NSCCs) plays a crucial role in membrane potential regulation. The basal activity of NSCCs is essential to effectively evoke depolarization in concert with KATP channel closure that is dependent on glucose metabolism. The present study summarizes recent findings regarding the roles of NSCCs in GSIS and GTP-binding protein coupled receptor-(GPCR) operated potentiation of GSIS. Key words: GPCR, Pancreatic β-cells, TRP channel, Insulin secretionTHE CONCEPT that glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is initiated by closure of the ATP-sensitive K + (KATP) channel as a result of an increase in the intracellular ATP/ADP ratio induced by glucose metabolism upon elevation of glucose concentration in the blood ( Fig. 1; the triggering pathway), was proposed a long time ago [1][2][3]. Inhibition of the KATP channel is followed by membrane depolarization and activation of voltage-dependent Ca 2+ channels (VDCCs) [4,5]. Opening of the VDCCs brings about firing of action potential, cytosolic Ca 2+ increase and initiation of GSIS [6,7]. The triggering pathway is followed by time-dependent increase in insulin secretion that is potentiated by glucose exposure (the second phase, potentiating pathway or KATP-independent pathway) [3,8] However, closure of the KATP channel alone is not sufficient to induce a shift in the membrane potential towards the threshold level and for the triggering pathway that can activate VDCCs, since membrane potential is theoretically determined by the overall balance of outward and inward currents. Modest background inward currents through opening of nonselective cation channels (NSCCs) are crucial for induction of membrane depolarization following KATP channel closure [9,10]. This idea further suggests that regulation of a class of NSCCs may play an important role in producing effective depolarization of the membrane. Several types of NSCCs have been reported to be expressed in pancreatic β-cells, which, in terms of ion selectivity, are permeable to Na + , K + , and Ca 2+ . In contrast to these ion channels, which have not been well studied, the classic-type ion channels; i.e., the voltage-dependent Na + channel, the voltage-dependent K + channel [11,12], the voltage-dependent Ca 2+ channel [13,14] and the KATP channel have attracted a large amount of interest for a long time, because the first three types of these ion channels play an important role in membrane excitability and the KATP

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Section: Trpm2 Channels As a Glp-1 Mechanism Potentiating Gsissupporting

confidence: 66%

Glucose and GTP-binding protein-coupled receptor cooperatively regulate transient receptor potential-channels to stimulate insulin secretion [Review]

et al. 2016

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“…Furthermore, ghrelin can modify the secretion of several pancreatic islet hormones that regulate blood glucose including the reduction of insulin secretion and stimulation of glucagon secretion (via either direct actions on pancreatic β cells [21,23,67] and α cells [24] or indirect actions on hypothalamic AgRP neurons [53] or somatostatin-secreting pancreatic δ cells [68]). However, insulin and glucagon levels in GC-β 1 AR -/-mice subjected to the 60% caloric restriction protocol were like those in similarly treated control groups.…”

Section: Discussionmentioning

confidence: 99%

β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

Mani¹,

Osborne-Lawrence²,

Vijayaraghavan³

et al. 2016

Journal of Clinical Investigation

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“…The expression of GHS-R1a in peripheral tissues indicates a direct peripheral mechanism for the physiological functions of circulating ghrelin. In pancreatic islets, ghrelin inhibits glucose-stimulated insulin secretion by activation of cAMP/TRPM2 signaling [26]. This effect is absent in the GHS-R1a null mice, suggesting a mechanism dependent on GHS-R1a.…”

Section: Fig8mentioning

confidence: 96%

Ghrelin Stimulates Hepatocyte Proliferation via Regulating Cell Cycle Through GSK3β/Β-Catenin Signaling Pathway

Wang

Zheng

Yin

et al. 2018

Cell Physiol Biochem

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Background/Aims: Obesity is associated with a reduction in ghrelin, a 28 aa gastric hormone. Whether reduced ghrelin contributes to the impaired proliferation of hepatocytes associated with obesity-related steatosis remains largely unknown. Here we examined the effects of ghrelin on the proliferation of hepatocytes derived from lean and obese mice. Methods: AML 12 cells or hepatocytes isolated from mice fed normal chow diet (NCD) or high fat diet (HFD) were used. Effects of ghrelin on hepatocyte proliferation were detected with CCK8 assay and EdU staining. Cell cycle was analyzed by flow cytometry. Levels of proliferation markers was examined by Western blot. Results: Growth hormone secretagogue receptor 1a (GHS-R1a) mRNA and protein were present in hepatocytes. Levels of GHS-R1a were increased upon ghrelin treatment. Ghrelin significantly increased hepatocyte proliferation measured by Cell Counting Kit-8(CCK8) assay and EdU staining in a dose- and time-dependent manner. Proportion of cells in S phase was markedly increased upon treatment with ghrelin. Ghrelin significantly increased levels of proliferating cell nuclear antigen (PCNA) and cyclin D1, while reducing p27 in hepatocytes from mice fed NCD or HFD. Deletion of GHS-R1a completely abolished the effects of ghrelin in cultured hepatocytes. Ghrelin stimulated the phosphorylation of glycogen synthase kinase 3 beta (GSK3β), leading to subsequent increase of nuclear β-catenin in hepatocytes derived from lean and obese mice. This effect was dependent on the GHS-R1a. Conclusion: Ghrelin activates GHS-R1a to stimulate hepatocyte proliferation via GSK3/β-catenin signaling pathway.

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The β-cell GHSR and downstream cAMP/TRPM2 signaling account for insulinostatic and glycemic effects of ghrelin

Cited by 51 publications

References 54 publications

Glucose and GTP-binding protein-coupled receptor cooperatively regulate transient receptor potential-channels to stimulate insulin secretion [Review]

Glucose and GTP-binding protein-coupled receptor cooperatively regulate transient receptor potential-channels to stimulate insulin secretion [Review]

β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

Ghrelin Stimulates Hepatocyte Proliferation via Regulating Cell Cycle Through GSK3β/Β-Catenin Signaling Pathway

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