GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.

Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.

Attenuation of histamine-induced airway effects by intranasal application of levocetirizine in mice.

The present study was performed to investigate the histamine-induced airway effect of levocetirizine, an active enantiomer of cetirizine, by intranasal application using ddY mice. Nasal rubbing and sneezing after histamine application into the nasal cavity were used as an index of histamine-induced airway effect in mice. Intranasal application of levocetirizine inhibited both nasal rubbing and sneezing concentration-dependently, and the ED50 values were 0.

Direct evidence for the up-regulation of Vps34 regulated by PKCgamma during short-term treatment with morphine.

In this study, we investigated whether PKCgamma could be associated with functional changes of vacuolar protein sorting 34 (Vps34) during morphine treatment using primary cultures of cerebral cortical neurons from mice. The immunoprecipitation analysis showed that p-PKCgamma and Vps34 are present together in molecular complexes. The treatment with morphine increases PKCgamma and Vps34 levels.

Low, but physiological, concentration of GLP-1 stimulates insulin secretion independent of the cAMP-dependent protein kinase pathway.

Glucagon-like peptide-1 (GLP-1) induces pancreatic insulin secretion via the cAMP-dependent protein kinase (PKA) pathway. However, the GLP-1 concentration used in the previous in vitro experiments was far from the in vivo concentrations. Alteration of plasma GLP-1 concentration at pM order lowers blood glucose concentration.

Up-regulation of L-type high voltage-gated calcium channel subunits by sustained exposure to 1,4- and 1,5-benzodiazepines in cerebrocortical neurons.

The aim of this study is to examine how sustained exposure to two 1,4-benzodiazepines (BZDs) with different action period, diazepam and brotizolam, and a 1,5-BZD, clobazam, affects L-type high voltage-gated calcium channel (HVCC) functions and its mechanisms using primary cultures of mouse cerebral cortical neurons. The sustained exposure to these three BZDs increased [(45)Ca2+] influx, which was due to the enhanced [(45)Ca2+] entry through L-type HVCCs but not through of Cav2.1 and Cav2.

Regional differences of L-type high voltage-gated calcium channel subunit expression in the mouse brain after chronic morphine treatment.

As functional changes in L-type high voltage-gated calcium channels (HVCCs) are recognized to be one of the major neurochemical modifications occurring in brains of animals with morphine physical dependence, this study attempts to examine whether regional difference in the expressions of HVCC subunits are produced in the brains under such pathological conditions. Scatchard analysis of [(3)H]PN200-110 binding showed increased Bmax values in the cerebral cortex and the mesolimbic region including the nucleus accumbence, which are brain regions participating in the development of morphine physical dependence, but not in the cerebellum. In the former two brain regions, alpha1C and alpha1D subunits of L-type HVCCs and alpha2/delta1 subunit increased, although decreases of alpha1B and alpha2/delta1 subunits were observed in the cerebellum.

Increase in diazepam binding inhibitor expression by sustained morphine exposure is mediated via mu-opioid receptors in primary cultures of mouse cerebral cortical neurons.

Our previous in vivo experiment demonstrates that chronic morphine treatment up-regulates diazepam binding inhibitor (DBI) transcripts in mouse cerebral cortex, although detailed mechanisms were unclear (Katsura et al. [1998] J. Neurochem.

Nateglinide and mitiglinide, but not sulfonylureas, induce insulin secretion through a mechanism mediated by calcium release from endoplasmic reticulum.

Nateglinide and mitiglinide (glinides) are characterized as rapid-onset and short-acting insulinotropic agents. Although both compounds do not have a sulfonylurea structure, it has been postulated that insulin secretion is preceded by their binding to Kir6.2/SUR1 complex, and a mechanism of insulin secretion of glinides has been accounted for by this pathway.

Increase in expression of alpha1 and alpha2/delta1 subunits of L-type high voltage-gated calcium channels after sustained ethanol exposure in cerebral cortical neurons.

Previous reports revealed up-regulation of L-type high voltage-gated calcium channels (HVCCs) in mouse brains with ethanol physical dependence. We investigated mechanisms of enhancement of L-type HVCC function using mouse cerebrocortical neurons exposed to 50 mM ethanol for 3 days and the brains of mouse physically dependent on ethanol. Ethanol facilitated 30 mM KCl-stimulated (45)Ca(2+) influx in dose- and duration-dependent manners, which was abolished by nifedipine, an inhibitor specific to L-type HVCCs, but not by inhibitors for other types of HVCCs.

Up-regulated L-type high voltage-gated calcium channels cause increase in diazepam binding inhibitor induced by sustained morphine exposure in mouse cerebrocortical neurons.

Mechanisms of increase in diazepam binding inhibitor (DBI) mRNA expression in mouse cerebrocortical neurons after sustained morphine exposure were investigated. Increases in DBI and its mRNA expressions induced by sustained morphine (0.3 microM) exposure for 3 days were completely abolished by naloxone and nifedipine, but not by omega-agatoxin VIA and omega-conotoxin GIVA.

Expression of beta-adrenergic receptor up-regulation is mediated by two different processes.

Mechanisms of up-regulation of beta-adrenergic receptors (beta-ARs) induced by sustained exposure to 10(-8) M nadolol, a non-selective beta-AR antagonist, were examined using mouse cerebrocortical neurons. Nadolol dose- and time-dependently increased [3H]CGP-12177 bindings to the particulate fractions. This increase occurred 6 h and attained its plateau 12 h after the exposure, whereas beta1- and beta2-AR mRNA significantly increased 24 h and attained their plateaus 3 days after the exposure.

First phase of glucose-stimulated insulin secretion from MIN 6 cells does not always require extracellular calcium influx.

To demonstrate an involvement of ATP-sensitive potassium (K(ATP)) channel-independent pathways in the first phase of glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells, the time course of GSIS from MIN6 cells was analyzed at 30-s sample intervals. GSIS was biphasic with the first phase being observed 120 to 390 s after glucose addition, peaking at 180 s, and with a shoulder at 240 to 330 s. Both 10 microM diazoxide and 3 microM verapamil completely inhibited tolbutamide- or glibenclamide-induced insulin secretion and suppressed the peak of the first phase of GSIS, but did not result in complete suppression.

[Functional significance of L-type high voltage-gated calcium channels after sustained ethanol exposure].

Functional significance of enhancement of L-type high voltage-gated calcium channels (HVCCs) induced by sustained ethanol exposure in mouse cerebral cortical neurons were focused in this review. Sustained ethanol exposure to the neurons induced up-regulation of L-type HVCCs, which was due to increased expression of a 1 and a 2/ delta 1 subunits. In the cerebral cortex prepared from alcohol-dependent mice, similar pattern of alterations in the expressed subunits examined were also found.

Increased expression of L-type high voltage-gated calcium channel alpha1 and alpha2/delta subunits in mouse brain after chronic nicotine administration.

We investigated the effect of chronic nicotine administration on high voltage-gated calcium channels (HVCCs) in the mouse cerebral cortex. The treatment significantly increased expression of alpha1C, alpha1D, alpha1F, and alpha2/delta1 subunits with no changes of beta4 subunit of L-type HVCCs. [(3)H]Diltiazem binding to the particulate fractions increased with increased Bmax value.

Ethanol physical dependence is accompanied by up-regulated expression of L-type high voltage-gated calcium channel alpha1 subunits in mouse brain.

We investigated how functional changes in high voltage-gated calcium channels (HVCCs) occurred in the cerebral cortex of mouse with ethanol physical dependence. The continuous treatment of mice with ethanol vapor for 8 days significantly increased the expressions of alpha1C, alpha1D, and alpha2/delta1 subunits of L-type HVCCs in association with decreased level of beta4 subunit of L-type HVCCs, although alpha1A and alpha1B subunits of P/Q- and N-type HVCCs, respectively, showed no alterations. [(3)H]Diltiazem binding to the particulate fractions increased with increased Bmax value and no changes of Kd value.

Functional proteins involved in regulation of intracellular Ca(2+) for drug development: chronic nicotine treatment upregulates L-type high voltage-gated calcium channels.

Neurochemical mechanisms underlying drug dependence and withdrawal syndrome remain unclear. In this review, we discuss how chronic nicotine exposure to neurons affects expression of diazepam binding inhibitor (DBI), an endogenous anxiogenic neuropeptide supposed to be a common substance participating drug dependence, and function of L-type high voltage-gated Ca(2+) channels (HVCCs). We also discuss the functional interaction between DBI and L-type HVCCs in nicotine dependence.

Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo.

Objectives: We examined whether hydroxyfasudil, a specific Rho-kinase inhibitor, exerts cardioprotective effect on coronary ischemia/reperfusion (I/R) injury and, if so, whether nitric oxide (NO) is involved.

Background: Recent studies have demonstrated that Rho-kinase is substantially involved in the pathogenesis of cardiovascular diseases; however, it remains to be examined whether it is also involved in ischemia/reperfusion (I/R) injury.

Methods: Canine subepicardial small arteries (SA, >or=100 microm) and arterioles (A, <100 microm) were observed by a charge-coupled device intravital microscope during I/R.

Pharmacological basis for management of drug dependence.

Neurochemical mechanisms underlying development of drug dependence and withdrawal syndrome remain unclear. Several clinical features of withdrawal syndrome, such as anxiety, are considered to be common among patients with drug dependence induced by different drugs of abuse. In the present study, we investigated whether diazepam-binding inhibitor (DBI), an endogenous anxiogenic neuropeptide, participates in the anxiety associated with drug dependence and its withdrawal symptoms.

[Functional involvement of endogenous anxiogenic neuropeptide in brains].

Neuronal GABA(A)/benzodiazepine and monoamine receptors participate in anxiety. Diazepam binding inhibitor (DBI), an endogenous anxiogenic neuropeptide, significantly increases in brains only after treatment with psychological stress, and this increase is completely abolished by benzodiazepines. Therefore, it is through that DBI may be involved in anxiogenesis produced by psychological stress.

Continuous exposure to nitric oxide enhances diazepam binding inhibitor mRNA expression in mouse cerebral cortical neurons.

Effects of sustained exposure to nitric oxide (NO) formed by long-term activation of N-methyl-D-aspartate (NMDA) receptors and liberated from a long-lasting NO generator, DETA NONOate, on diazepam binding inhibitor (DBI) and its mRNA expressions were examined using mouse cerebral cortical neurons. Long-term exposure to NMDA increased DBI mRNA expression, and NO synthase inhibitors dose-dependently inhibited this increase. DETA NONOate dose-dependently increased DBI mRNA expression when exposing the neurons to this agent for 3 days and a maximal enhancement of the expression was found at 100 microM of the NO generator.

Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity.

The effect of endogenous nitric oxide synthase (NOS) on cardiac contractility and architecture has been a matter of debate. A role for NOS in cardiac hypertrophy has recently been demonstrated by studies which have shown hypertrophic cardiomyopathy (HCM) with altered contractility in constitutive NOS (cNOS) knockout mice. Caveolin-3, a strong inhibitor of all NOS isoforms, is expressed in sarcolemmal caveolae microdomains and binds to cNOS in vivo: endothelial nitric oxide synthase (eNOS) in cardiac myocytes and neuronal nitric oxide synthase (nNOS) in skeletal myocytes.

L-type high voltage-gated calcium channels cause an increase in diazepam binding inhibitor mRNA expression after sustained exposure to ethanol in mouse cerebral cortical neurons.

Mechanisms for increase in diazepam binding inhibitor (DBI) mRNA expression after sustained exposure to ethanol (EtOH) were investigated. Increases in 30 mM KCl-induced [45Ca(2+)] influx and DBI mRNA expression after EtOH (50 mM) exposure for 3 days were completely abolished by nifedipine, but not by omega-agatoxin VIA and omega-conotoxin GIVA. These results indicate that EtOH-induced increase in DBI mRNA expression is mediated via increased Ca(2+) entry through up-regulated L-type high voltage-gated calcium channels.