scholarly journals Glucagon‑like peptide‑1 potentiates glucose‑stimulated insulin secretion via the transient receptor potential melastatin 2 channel

2017 ◽  
Author(s):  
Bo Pang ◽  
Sungjoon Kim ◽  
Daiqing Li ◽  
Zejun Ma ◽  
Bei Sun ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Transient Receptor ◽  
Glucose Stimulated Insulin Secretion

scholarly journals The proposed channel-enzyme transient receptor potential melastatin 2 does not possess ADP ribose hydrolase activity

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Iordan Iordanov ◽  
Csaba Mihályi ◽  
Balázs Tóth ◽  
László Csanády
Keyword(s):  
Cell Death ◽  
Insulin Secretion ◽  
Transient Receptor Potential ◽  
Channel Gating ◽  
Receptor Potential ◽  
Cation Channel ◽  
Chimeric Proteins ◽  
Transient Receptor Potential Melastatin ◽  
Biochemical Studies ◽  
Transient Receptor

Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca2+-permeable cation channel essential for immunocyte activation, insulin secretion, and postischemic cell death. TRPM2 is activated by ADP ribose (ADPR) binding to its C-terminal cytosolic NUDT9-homology (NUDT9H) domain, homologous to the soluble mitochondrial ADPR pyrophosphatase (ADPRase) NUDT9. Reported ADPR hydrolysis classified TRPM2 as a channel-enzyme, but insolubility of isolated NUDT9H hampered further investigations. Here we developed a soluble NUDT9H model using chimeric proteins built from complementary polypeptide fragments of NUDT9H and NUDT9. When expressed in E.coli, chimeras containing up to ~90% NUDT9H sequence remained soluble and were affinity-purified. In ADPRase assays the conserved Nudix-box sequence of NUDT9 proved essential for activity (kcat~4-9s-1), that of NUDT9H did not support catalysis. Replacing NUDT9H in full-length TRPM2 with soluble chimeras retained ADPR-dependent channel gating (K1/2~1-5 μM), confirming functionality of chimeric domains. Thus, TRPM2 is not a 'chanzyme'. Chimeras provide convenient soluble NUDT9H models for structural/biochemical studies.

scholarly journals A TRPM4 Inhibitor 9-Phenanthrol Inhibits Glucose- and Glucagon-Like Peptide 1-Induced Insulin Secretion from Rat Islets of Langerhans

2017 ◽  
Vol 2017 ◽  
pp. 1-5 ◽  
Author(s):  
Zuheng Ma ◽  
Anneli Björklund ◽  
Md. Shahidul Islam
Keyword(s):  
Insulin Secretion ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Monovalent Cation ◽  
Major Effect ◽  
Hyperinsulinemic Hypoglycemia ◽  
Rat Islets ◽  
Glucagon Like Peptide 1 ◽  
Transient Receptor ◽  
Rat Islets Of Langerhans

Pancreatic β-cells express several ion channels of the transient receptor potential family, which play important roles in mediating the stimulus-secretion coupling. One of these channels, the TRPM4 is a Ca2+-activated monovalent cation channel. This channel is inhibited by 9-phenanthrol, which also inhibits the TMEM16a Cl− channel, and activates the Ca2+-activated K+ channel, Kca3.1. The net effects of ion-channel modulation by 9-phenantherol on the insulin secretion remain unclear. We tested the effects of 9-phenanthrol on glucose- and GLP-1-induced insulin secretion from isolated rat islets in static incubations. When applied to the islets in the presence of 3.3 mM glucose, 9-phenanthrol caused a small increase in insulin secretion (~7% of the insulin secretion stimulated by 10 mM glucose). 10 μM 9-phenanthrol did not inhibit glucose- or GLP-1-induced insulin secretion. 20 μM and 30 μM 9-phenanthrol inhibited glucose-induced insulin secretion by ~80% and ~85%, respectively. Inhibition of the GLP-1-induced insulin secretion by 20 μM and 30 μM 9-phenanthrol was 65% and 94%, respectively. Our study shows that the major effect of 9-phenanthrol on the islets is a strong inhibition of insulin secretion, and we speculate that compounds related to 9-phenanthrol may be potentially useful in treating the pancreatogenous hyperinsulinemic hypoglycemia syndromes.

scholarly journals Cinnamaldehyde Induces Release of Cholecystokinin and Glucagon-Like Peptide 1 by Interacting with Transient Receptor Potential Ankyrin 1 in a Porcine Ex-Vivo Intestinal Segment Model

Animals ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 2262
Author(s):  
Elout Van Liefferinge ◽  
Maximiliano Müller ◽  
Noémie Van Noten ◽  
Jeroen Degroote ◽  
Shahram Niknafs ◽  
...  
Keyword(s):  
Small Intestine ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Receptor Potential ◽  
Intestinal Segment ◽  
Gastric Function ◽  
Segment Model ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Transient Receptor

Cinnamaldehyde and capsaicin have been reported to exert effects on the gastric function, mediated by the interaction with transient receptor potential ankyrin channel 1 (TRPA1) and transient receptor potential vanilloid channel 1 (TRPV1), respectively. This study examined whether these compounds could trigger the release of cholecystokinin (CCK) and/or glucagon-like peptide 1 (GLP-1) in the pig’s gut in a porcine ex-vivo intestinal segment model. Furthermore, it was verified whether this response was mediated by TRPA1 or TRPV1 by using the channel’s antagonist. These gut peptides play a key role in the “intestinal brake", a feedback mechanism that influences the function of proximal parts of the gut. Structural analogues of cinnamaldehyde were screened as well, to explore structure-dependent activation. Results showed a significant effect of capsaicin on GLP-1 release in the proximal small intestine, TRPV1 independent. TRPA1 showed to be strongly activated by cinnamaldehyde, both in proximal and distal small intestine, evidenced by the release of CCK and GLP-1, respectively. Out of all structural derivates, cinnamaldehyde showed the highest affinity for TRPA1, which elucidates the importance of the α,β-unsaturated aldehyde moiety. In conclusion, cinnamaldehyde as a TRPA1 agonist, is a promising candidate to modulate gastric function, by activating intestinal brake mechanisms.

The TRPM7 Channel in the Nervous and Cardiovascular Systems

2020 ◽  
Vol 21 (10) ◽  
pp. 985-992 ◽  
Author(s):  
Koichi Inoue ◽  
Zhi-Gang Xiong ◽  
Takatoshi Ueki
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Kinase Domain ◽  
Cellular Functions ◽  
Transient Receptor Potential Melastatin ◽  
Cation Permeability ◽  
Cardiovascular Systems ◽  
Transient Receptor ◽  
Excitatory Responses ◽  
Dual Operations

: Transient receptor potential melastatin 7 (TRPM7), along with the closely related TRPM6, are unique channels that have dual operations: cation permeability and kinase activity. In contrast to the limited tissue distribution of TRPM6, TRPM7 is widely expressed among tissues and is therefore implicated in a variety of cellular functions physiologically and pathophysiologically. The discovery of TRPM7’s unique structure imparting dual ion channel and kinase activities shed light onto novel and peculiar biological functions, such as Mg2+ homeostasis, cellular Ca2+ flickering, and even intranuclear transcriptional regulation by a cleaved kinase domain translocated to nuclei. Interestingly, at a higher level, TRPM7 participates in several biological processes in the nervous and cardiovascular systems, in which excitatory responses in neurons and cardiomyocytes are critical for their function. Here, we review the roles of TRPM7 in cells involved in the nervous and cardiovascular systems and discuss its potential as a future therapeutic target.

Pharmacological Inhibition of Transient Receptor Potential Melastatin 2 (TRPM2) Channels Attenuates Diabetes-induced Cognitive Deficits in Rats: A Mechanistic Study

2020 ◽  
Vol 17 (3) ◽  
pp. 249-258 ◽  
Author(s):  
Pavan Thapak ◽  
Mahendra Bishnoi ◽  
Shyam S. Sharma
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Deficits ◽  
Ache Activity ◽  
Transient Receptor Potential ◽  
Mrna Level ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channels ◽  
Transient Receptor ◽  
Gsk 3Β

Background: Diabetes is a chronic metabolic disorder affecting the central nervous system. A growing body of evidence has depicted that high glucose level leads to the activation of the transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach. Objective: The present study intended to investigate the effects of 2-aminoethoxydiphenyl borate (2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment. Methods: Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were randomly divided into the treatment group, model group and age-matched control and pre se group. 2-APB treatment was given for three weeks to the animals. After 10 days of behavioural treatment, parameters were performed. Animals were sacrificed at 10th week of diabetic induction and the hippocampus and cortex were isolated. After that, protein and mRNA expression study was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex. Results: : Our study showed the 10th week diabetic animals developed cognitive impairment, which was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2 mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex. However, memory associated proteins were down-regulated, namely Ca2+/calmodulin-dependent protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3β-Ser9), cAMP response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95). Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF) were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. A three-week treatment with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic rats. Moreover, 2-APB also down-regulated the expression of TRPM2 mRNA and protein in the hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic animals. Moreover, the 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3β (Ser9), CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic animals. Conclusion: : This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes- induced cognitive deficits. Inhibition of TRPM2 channels reduced the calcium associated downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetesinduced cognitive impairment.

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