scholarly journals Neonatal Diabetes in Patients Affected by Liang-Wang Syndrome Carrying KCNMA1 Variant p.(Gly375Arg) Suggest a Potential Role of Ca2+ and Voltage-Activated K+ Channel Activity in Human Insulin Secretion

2021 ◽  
Vol 43 (2) ◽  
pp. 1036-1042
Author(s):  
Chiara Mameli ◽  
Roberta Cazzola ◽  
Luigina Spaccini ◽  
Valeria Calcaterra ◽  
Maddalena Macedoni ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Human Insulin ◽  
Potential Role ◽  
Neonatal Diabetes ◽  
K Channel ◽  
Heterozygous Mutation ◽  
Gene Encoding ◽  
Mitochondrial Functions ◽  
K Current

Liang-Wang syndrome (LIWAS) is a polymalformative syndrome first described in 2019 caused by heterozygous mutation of the KCNMA1 gene encoding the Ca2+ and voltage-activated K+ channel (BKC). The KCNMA1 variant p.(Gly356Arg) abolishes the function of BKC and blocks the generation of K+ current. The phenotype of this variant includes developmental delay, and visceral and connective tissue malformations. So far, only three cases of LWAS have been described, one of which also had neonatal diabetes (ND). We present the case of a newborn affected by LIWAS carrying the p.(Gly375Arg) variant who manifested diabetes in the first week of life. The description of our case strongly increases the frequency of ND in LIWAS patients and suggests a role of BK inactivation in human insulin secretion. The knowledge on the role of BKC in insulin secretion is very poor. Analyzing the possible mechanisms that could explain the association of LIWAS with ND, we speculate that BK inactivation might impair insulin secretion through the alteration of ion-dependent membrane activities and mitochondrial functions in β-cells, as well as the impaired intra-islet vessel reactivity.

scholarly journals Regulation of Insulin Secretion and β-Cell Mass by Activating Signal Cointegrator 2

2006 ◽  
Vol 26 (12) ◽  
pp. 4553-4563 ◽  
Author(s):  
Seon-Yong Yeom ◽  
Geun Hyang Kim ◽  
Chan Hee Kim ◽  
Heun Don Jung ◽  
So-Yeon Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Endocrine Cells ◽  
Potential Role ◽  
Cell Mass ◽  
Dominant Negative ◽  
Transcriptional Coactivator ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass

ABSTRACT Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes). In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic β-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2+/− mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2+/− mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2+/− islets. These results suggest that ASC-2 regulates insulin secretion and β-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.

scholarly journals Potential role of luminal potassium in tubuloglomerular feedback.

1997 ◽  
Vol 8 (12) ◽  
pp. 1831-1837 ◽  
Author(s):  
V Vallon ◽  
H Osswald ◽  
R C Blantz ◽  
S Thomson
Keyword(s):  
Potential Role ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
K Channel ◽  
Thick Ascending Limb ◽  
Retrograde Perfusion ◽  
Luminal Membrane ◽  
K Concentration ◽  
Tubular Flow

Transport through the Na+-2Cl(-)-K+ cotransporter in the luminal membrane of macula densa cells is considered critical for tubuloglomerular feedback (TGF). Although various studies could support the importance of luminal Na+ and Cl-, the role of luminal K+ in TGF has not been thoroughly addressed. The study presented here examines this issue in nephrons with superficial glomeruli of anesthetized male Munich-Wistar-Frömter rats. Ambient Na+ concentration in early distal tubular fluid was approximately 22 mM, suggesting collection sites relatively close to the macula densa segment. First, it was found that ambient early distal tubular K+ concentration is approximately 1.3 mM, i.e., close to the K+ affinity of the Na+-2Cl(-)-K+ cotransporter in the thick ascending limb. Second, it was observed that a change in late proximal tubular flow rate, i.e., a maneuver that is known to induce a TGF response, significantly alters early distal tubular K+ concentration. Third, previous experiments failed to show an inhibition in TGF response during retrograde perfusion of the macula densa with K+-free solutions. Because of a potential K+ influx into the lumen between the perfusion site and the macula densa, however, the K+ channel blocker U37883A was added to the K+-free perfusate. TGF response was assessed as the fall in nephron filtration rate in response to retrograde perfusion of the macula densa segment from early distal tubular site. It was observed that luminal U37883A (100 microM) significantly attenuated TGF. Because adding 5 mM KCl to the perfusate restored TGF in the presence of U37883A and because the inhibitory action of U37883A on tubular K+ secretion was confirmed, the effect of U37883A on TGF was most likely caused by inhibition of K+ influx into the perfused segment, which decreased luminal K+ concentration at the macula densa. The present findings support a potential role for luminal K+ in TGF, which is in accordance with a transmission of the TGF signal across the macula densa via Na+-2Cl(-)-K+ cotransporter.

scholarly journals Cardiac preconditioning with 4-h, 17°C ischemia reduces [Ca2+]i load and damage in part via KATP channel opening

2002 ◽  
Vol 282 (6) ◽  
pp. H1961-H1969 ◽  
Author(s):  
Qun Chen ◽  
Amadou K. S. Camara ◽  
Jianzhong An ◽  
Matthias L. Riess ◽  
Enis Novalija ◽  
...  
Keyword(s):  
Infarct Size ◽  
Potential Role ◽  
K Channel ◽  
Moderate Hypothermia ◽  
Channel Opening ◽  
Cardioprotective Effects ◽  
Hypothermic Storage ◽  
Cardiac Preconditioning

Brief ischemia before normothermic ischemia protects hearts against reperfusion injury (ischemic preconditioning, IPC), but it is unclear whether it protects against long-term moderate hypothermic ischemia. We explored in isolated guinea pig hearts 1) the influence of two 2-min periods of normothermic ischemia before 4 h, 17°C hypothermic ischemia on cardiac cytosolic [Ca2+], mechanical and metabolic function, and infarct size, and 2) the potential role of KATP channels in eliciting cardioprotection. We found that IPC before 4 h moderate hypothermia improved myocardial perfusion, contractility, and relaxation during normothermic reperfusion. Protection was associated with markedly reduced diastolic [Ca2+] loading throughout both hypothermic storage and reperfusion. Global infarct size was markedly reduced from 36 ± 2 (SE)% to 15 ± 1% with IPC. Bracketing ischemic pulses with 200 μM 5-hydroxydecanoic acid or 10 μM glibenclamide increased infarct size to 28 ± 3% and 26 ± 4%, respectively. These results suggest that brief ischemia before long-term hypothermic storage adds to the cardioprotective effects of hypothermia and that this is associated with decreased cytosolic [Ca2+] loading and enhanced ATP-sensitive K channel opening.

scholarly journals TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy

2017 ◽  
Vol 114 (43) ◽  
pp. 11524-11529 ◽  
Author(s):  
Cheryl E. G. Leyns ◽  
Jason D. Ulrich ◽  
Mary B. Finn ◽  
Floy R. Stewart ◽  
Lauren J. Koscal ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Potential Role ◽  
Piriform Cortex ◽  
Tau Pathology ◽  
Gene Encoding ◽  
Gene Expression Analyses ◽  
Unexpected Findings ◽  
Microglial Response ◽  
The Brain

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) were recently found to increase the risk for developing Alzheimer’s disease (AD). In the brain, TREM2 is predominately expressed on microglia, and its association with AD adds to increasing evidence implicating a role for the innate immune system in AD initiation and progression. Thus far, studies have found TREM2 is protective in the response to amyloid pathology while variants leading to a loss of TREM2 function impair microglial signaling and are deleterious. However, the potential role of TREM2 in the context of tau pathology has not yet been characterized. In this study, we crossed Trem2+/+ (T2+/+) and Trem2−/− (T2−/−) mice to the PS19 human tau transgenic line (PS) to investigate whether loss of TREM2 function affected tau pathology, the microglial response to tau pathology, or neurodegeneration. Strikingly, by 9 mo of age, T2−/−PS mice exhibited significantly less brain atrophy as quantified by ventricular enlargement and preserved cortical volume in the entorhinal and piriform regions compared with T2+/+PS mice. However, no TREM2-dependent differences were observed for phosphorylated tau staining or insoluble tau levels. Rather, T2−/−PS mice exhibited significantly reduced microgliosis in the hippocampus and piriform cortex compared with T2+/+PS mice. Gene expression analyses and immunostaining revealed microglial activation was significantly attenuated in T2−/−PS mice, and there were lower levels of inflammatory cytokines and astrogliosis. These unexpected findings suggest that impairing microglial TREM2 signaling reduces neuroinflammation and is protective against neurodegeneration in the setting of pure tauopathy.

scholarly journals Stress and sex: does cortisol mediate sex change in fish?

Reproduction ◽  
2017 ◽  
Vol 154 (6) ◽  
pp. R149-R160 ◽  
Author(s):  
Alexander Goikoetxea ◽  
Erica V Todd ◽  
Neil J Gemmell
Keyword(s):  
Potential Role ◽  
Current Knowledge ◽  
Sex Change ◽  
Control Fish ◽  
Lifetime Reproductive Success ◽  
Gene Encoding ◽  
Environmental Signals ◽  
Key Factor ◽  
Social Environmental

Cortisol is the main glucocorticoid (GC) in fish and the hormone most directly associated with stress. Recent research suggests that this hormone may act as a key factor linking social environmental stimuli and the onset of sex change by initiating a shift in steroidogenesis from estrogens to androgens. For many teleost fish, sex change occurs as a usual part of the life cycle. Changing sex is known to enhance the lifetime reproductive success of these fish and the modifications involved (behavioral, gonadal and morphological) are well studied. However, the exact mechanism behind the transduction of the environmental signals into the molecular cascade that underlies this singular process remains largely unknown. We here synthesize current knowledge regarding the role of cortisol in teleost sex change with a focus on two well-described transformations: temperature-induced masculinization and socially regulated sex change. Three non-mutually exclusive pathways are considered when describing the potential role of cortisol in mediating teleost sex change: cross-talk between GC and androgen pathways, inhibition of aromatase expression and upregulation ofamh(the gene encoding anti-Müllerian hormone). We anticipate that understanding the role of cortisol in the initial stages of sex change will further improve our understanding of sex determination and differentiation across vertebrates, and may lead to new tools to control fish sex ratios in aquaculture.

Potential role of skeletal muscle glucose metabolism on the regulation of insulin secretion

2014 ◽  
Vol 15 (7) ◽  
pp. 587-597 ◽  
Author(s):  
M. L. Mizgier ◽  
M. Casas ◽  
A. Contreras-Ferrat ◽  
P. Llanos ◽  
J. E. Galgani
Keyword(s):  
Skeletal Muscle ◽  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Potential Role

Inhibition of α-adrenergic responses in the rat liver by lipophilic K+ channel blockers or depolarizing Cl− gradients. Evidence for a potential-sensitive step in the signal transduction path

1993 ◽  
Vol 71 (5-6) ◽  
pp. 229-235 ◽  
Author(s):  
Ceredwyn E. Hill ◽  
David O. Ajikobi
Keyword(s):  
Signal Transduction ◽  
Rat Liver ◽  
Potential Role ◽  
Portal Pressure ◽  
K Channel ◽  
Second Phase ◽  
Channel Blockers ◽  
Adrenergic Stimulation ◽  
Glucose Release

To study the role of K+ channels and membrane potential in α-adrenergic responses of the rat liver, lipophilic K+ channel blockers quinidine and 4-aminopyridine were used or external Cl− was replaced with gluconate, an impermeant ion. Glucose release, O2 uptake, portal pressure, and K+ flux were measured in the isolated perfused liver. The α-agonist phenylephrine caused biphasic changes in each parameter, a fast transient followed by sustained elevated responses. Infusion of 5 mM 4-aminopyridine, 0.1 mM quinidine, or gluconate prior to phenylephrine inhibited each parameter, with the greatest inhibition occurring during the second phase. A similar pattern was seen with 2 mM EGTA. This contrasts with the full inhibition of all responses following exposure to the α-antagonist phentolamine. Infusion of each inhibitor at the peak of the sustained phase inhibited all responses. Phenylephrine-stimulated release of K+ was augmented in the presence of EGTA and was inhibited by 4-aminopyridine or quinidine. In contrast, β-adrenergic stimulation of glucose release and K+ flux were not affected by the K+ channel blockers. Phenylephrine-stimulated glucose release from hepatocyte suspensions decreased by about 50% in the presence of 4-aminopyridine, EGTA, or gluconate. The results are discussed in terms of a potential role for K+ channels in α-adrenergic signal transduction in the liver.Key words: perfusion, hepatocyte, glycogenosis, haemodynamics, pinacidil.

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