Despite many migraine-specific treatments that became available over the past 5 years, many patients still suffer from debilitating migraine. Emerging and future directions of migraine research and treatment should consider different aspects including revising the headache diagnostic criteria to reflect disease burden and prognosis, developing biomarkers, including genetic, serum, imaging, and deep phenotyping biomarkers to facilitate personalized medicine for headache treatment. Additionally, research should also emphasize identifying novel treatment targets for drug development. In this chapter, we provide an overview of current studies and controversies in the diagnosis of migraine and available research on potential migraine biomarkers. We also discuss potential treatment targets for migraine, including CGRP, PACAP, orexin, non-μ opioid receptors, nitric oxide, BKCa channel, KATP channel, amylin, TRP channels, prolactin, PAR-2, and other potential targets.

Maturity-onset diabetes of the young (MODY) is an inherited form of diabetes resulting from a mutation in a single gene. ABCC8-MODY is caused by mutations in the ABCC8 gene, which encodes sulfonylurea receptor 1 (SUR1), a regulatory component of the ATP-sensitive potassium (KATP) channel found in beta cells. In ABCC8-MODY, mutations in the ABCC8 gene interfere with insulin secretion in response to glucose. Recent evidence suggests that therapy with GLP-1 receptor agonists (GLP-1 RAs) may be beneficial in ABCC8-MODY. This report presents a successful treatment of a 49-year-old woman diagnosed with ABCC8-MODY using the GLP-1 RA semaglutide. The patient, who had been previously receiving insulin therapy, experienced significant improvements in glycemic control and weight loss after transitioning to semaglutide. GLP-1 RAs potentially enhance insulin secretion in ABCC8-MODY by activating multiple signaling pathways involved in insulin secretion. The report highlights the potential of GLP-1 RA therapy as an alternative to sulfonylureas and insulin for individuals with ABCC8-MODY. GLP-1 RAs have previously demonstrated benefits in other forms of MODY. Understanding the molecular mechanisms through which GLP-1 RAs promote insulin secretion, including their effects on KATP channels and activation of PKA and Epac signaling, offers valuable insights into their therapeutic effects.

Type 2 diabetes is characterized by insulin hypersecretion followed by reduced glucose-stimulated insulin secretion (GSIS). Here we show that acute stimulation of pancreatic islets with the insulin secretagogue dextrorphan (DXO) or glibenclamide enhances GSIS, whereas chronic treatment with high concentrations of these drugs reduce GSIS but protect islets from cell death. Bulk RNA sequencing of islets shows increased expression of genes for serine-linked mitochondrial one-carbon metabolism (OCM) after chronic, but not acute, stimulation. In chronically stimulated islets, more glucose is metabolized to serine than to citrate, and the mitochondrial ATP/ADP ratio decreases, whereas the NADPH/NADP+ ratio increases. Activating transcription factor-4 (Atf4) is required and sufficient to activate serine-linked mitochondrial OCM genes in islets, with gain- and loss-of-function experiments showing that Atf4 reduces GSIS and is required, but not sufficient, for full DXO-mediated islet protection. In sum, we identify a reversible metabolic pathway that provides islet protection at the expense of secretory function.

The ATP-sensitive K+ (KATP) channel is a key regulator of hormone secretion from pancreatic islet endocrine cells. Using direct measurements of KATP channel activity in pancreatic β cells and the lesser-studied α cells, from both humans and mice, we provide evidence that a glycolytic metabolon locally controls KATP channels on the plasma membrane. The two ATP-consuming enzymes of upper glycolysis, glucokinase and phosphofructokinase, generate ADP that activates KATP. Substrate channeling of fructose 1,6-bisphosphate through the enzymes of lower glycolysis fuels pyruvate kinase, which directly consumes the ADP made by phosphofructokinase to raise ATP/ADP and close the channel. We further show the presence of a plasma membrane-associated NAD+/NADH cycle whereby lactate dehydrogenase is functionally coupled to glyceraldehyde-3-phosphate dehydrogenase. These studies provide direct electrophysiological evidence of a KATP-controlling glycolytic signaling complex and demonstrate its relevance to islet glucose sensing and excitability.

MODY3 is a monogenic hereditary form of diabetes caused by mutations in the transcription factor HNF1A. The patients progressively develop hyperglycemia due to perturbed insulin secretion, but the pathogenesis is unknown. Using patient-specific hiPSCs, we recapitulate the insulin secretion sensitivity to the membrane depolarizing agent sulfonylurea commonly observed in MODY3 patients. Unexpectedly, MODY3 patient-specific HNF1A+/R272C β cells hypersecrete insulin both in vitro and in vivo after transplantation into mice. Consistently, we identified a trend of increased birth weight in human HNF1A mutation carriers compared with healthy siblings. Reduced expression of potassium channels, specifically the KATP channel, in MODY3 β cells, increased calcium signaling, and rescue of the insulin hypersecretion phenotype by pharmacological targeting ATP-sensitive potassium channels or low-voltage-activated calcium channels suggest that more efficient membrane depolarization underlies the hypersecretion of insulin in MODY3 β cells. Our findings identify a pathogenic mechanism leading to β cell failure in MODY3.

Current treatments for chronic pain are unsatisfactory, therefore, new therapeutics are urgently needed. Our previous study indicated that KATP channel openers have analgesic effects, but the underlying mechanism has not been elucidated. We speculated that KATP channel openers might increase suppressor of cytokine signaling (SOCS)-3 expression to induce inflammatory tolerance and attenuate chronic pain. Postoperative pain was induced by plantar incision to establish a chronic pain model. Growth arrest-specific 6 (Gas6)-/- and Axl-/- mice were used for signaling studies. The microglia cell line BV-2 was cultured for the in vitro experiments. The KATP channel opener significantly attenuated incision-induced mechanical allodynia in mice associated with the upregulated expression of SOCS3. Opening KATP channels induced the expression of SOCS3 in the Gas6/Axl signaling pathway in microglia, inhibited incision-induced mechanical allodynia by activating the Gas6/Axl-SOCS3 signaling pathway, and induced inflammatory tolerance to relieve neuroinflammation and postoperative pain. We demonstrated that opening of the KATP channel opening activated Gas6/Axl/SOCS3 signaling to induce inflammatory tolerance and relieve chronic pain. We explored a new target for anti-inflammatory and analgesic effects by regulating the innate immune system and provided a theoretical basis for clinical preemptive analgesia.

Potassium ion channels are extensively involved in the regulation of epileptic seizures. The small conductance calcium-sensitive potassium channels (SK channels) and ATP-sensitive potassium (KATP) channels are activated by calcium ion entry and decrease ATP levels, respectively. These channels can underlie the post-burst afterhyperpolarization and be upregulated during seizures, providing negative feedback during epileptic activity. Using the whole-cell patch-clamp method in rat brain slices, we investigated the effect of SK- and KATP-affecting drugs on seizure-like events (SLEs) in the 4-aminopyridine model of epileptic seizures in vitro. We demonstrate that SK and KATP channels contribute to sustaining the high-frequency firing of the principal neurons in the deep layers of the entorhinal cortex during injections of depolarizing current and epileptiform discharges. Neither the pharmacological blockade nor the activation of these channels was able to prevent the epileptiform activity in brain slices. However, the blockade of KATP channels increases the SLE duration, suggesting that these channels may contribute to the termination of SLEs. Thus, KATP channels can be considered a promising target for pharmacological interventions for the treatment of epilepsy.

Peripheral neuropathy induced by chemotherapeutic agents is the most common dose-limiting adverse effect observed in patients during and after treatment of malignancies. Many flavones have been reported to ameliorate neuropathy of different origin in experimental animals and their possible mode of action explored. The present study aims to investigate 7,3\'-dihydroxyflavone for its anti-neuropathic effect against paclitaxel induced peripheral neuropathy in mice by employing behavioural tests such as mechanical allodynia, cold allodynia and thermal hyperalgesia. The possible involvement of GABAA, KATP channels and adenosine receptors in the anti-neuropathic effect of 7,3\'-dihydroxyflavone was also studied by employing suitable interacting drugs. Treatment with 7,3\'-dihydroxyflavone (50, 100 or 200 mg/kg, s.c) significantly and dose-dependently reduced the paw withdrawal response score in both mechanical and cold allodynia and also increased the tail flick response time in thermal hyperalgesia due to paclitaxel-induced neuropathy. Pre-treatment with glibenclamide (10 mg/kg, i.p), caffeine (50 mg/kg, i.p) or bicuculline (2 mg/kg, i.p) significantly reversed the anti-neuropathic effect of 7,3\'-dihydroxyflavone in behavioral tests. In conclusion, the present investigation identified 7,3\'-dihydroxyflavone as a potential candidate with anti-neuropathic effect against paclitaxel induced peripheral neuropathy involving KATP channels, adenosine and GABAA receptors.

Elucidating the taste sensing systems in chickens will enhance our understanding of poultry nutrition and improve the feeding strategies used in poultry farming. It is known that chickens lack the sweet taste receptor subunit, taste receptor type 1 member 2 (T1R2), in their genome. Thus, the present study investigated T1R2-independent sweet-sensing pathways in chickens. RT-PCR analysis revealed that glucose transporters known to play an important role in T1R2-independent sweet sensing in mammals-namely sodium-glucose cotransporter 1 (SGLT1) and ATP-gated K+ channel subunits-are expressed in the palate, the main taste organ in chickens. In behavioral tests, chickens slightly preferred glucose, galactose, sucrose, maltose, lactose, and stevioside, while high doses of sucrose and fructose were rejected. Chickens did not show any preference for noncaloric sweeteners or sugar alcohol, such as acesulfame K, aspartame, saccharin, sucralose, or sorbitol. The preference for galactose was inhibited by an inhibitor of SGLT1 in a dose-dependent manner. In addition, we found that glucagon-like peptide 1 (GLP-1) and mRNA of the GLP-1 receptor, which are involved specifically in sweet transmission in mice, are also present in the oral tissues of chickens. The present results imply that chickens can sense various sweet compounds via T1R2-independent pathways in oral tissues.

Patients with Alzheimer\'s disease (AD) demonstrate severely impaired olfactory systems, which occur in the early stages of the disease. Olfactory bulbectomy (OBX) in mice elicits cognitive deficits, and reduces cholinergic activity in the hippocampus. Here, we confirmed that the novel AD drug memantine rescues cognitive deficits via ATP-sensitive potassium (KATP) channel inhibition in OBX mice. Repeated memantine administration at 1-3 mg/kg p.o. for 14 days starting at 10 days after OBX surgery significantly rescued cognitive deficits in OBX mice, as assessed using Y-maze, novel object recognition, and passive avoidance tasks. Consistent with the rescued cognitive deficits in OBX mice, long-term potentiation (LTP) in the hippocampal cornu ammonis (CA) 1 region was markedly restored with memantine administration. As demonstrated by immunoblotting, the reductions of calcium/calmodulin-dependent protein kinase II (CaMKII) α (Thr-286) autophosphorylation and calcium/calmodulin-dependent protein kinase IV (CaMKIV; Thr-196) phosphorylation in the CA1 region of OBX mice were significantly restored with memantine. Conversely, pre-treatment with pinacidil, a KATP channel opener, failed to reinstate hippocampal LTP and CaMKII/CaMKIV activities in the CA1 region. Finally, improvement of cognitive deficits by memantine treatments was observed in OBX-operated Kir6.1 heterozygous (+/-) mice but not in OBX-operated Kir6.2 heterozygous (+/-) mice. Overall, our study demonstrates that memantine rescues OBX-induced cognitive deficits via Kir6.2 channel inhibition in the CA1 region.