Biomedical subjects

Akemichi Baba

Publications and source records attributed to Akemichi Baba.

At least 55 records · Page 3Linked to original sources

PubMed2004

PACAP activates Rac1 and synergizes with NGF to activate ERK1/2, thereby inducing neurite outgrowth in PC12 cells.

The mechanisms linked to the neuritogenic effect of PACAP acting in synergy with NGF were analyzed in PC12 cells. Recently, we have shown that PACAP synergizes with NGF to stimulate PACAP gene transcription and neurite outgrowth, differentially dependent on both the ERK1/2 and p38 MAP kinase pathways in PC12 cells. This suggests that PACAP modulates mitogen signaling pathways governing cell differentiation, in part through MAP kinase activation and an autocrine mechanism. Here, we studied the mechanism of the underlying neuritogenic actions of PACAP. PACAP induced transient activation of Rac1, a small GTPase involved in neurite outgrowth, in a PI3-kinase-independent manner, and stimulated accumulation of active Rac1 at filamentous actin-rich protrusions on the cell surface to induce subsequent neurite formation. PACAP had no additional effect on the activity of Rac1 beyond the effect of NGF and failed to activate Ras or Cdc42. By contrast, simultaneous treatment with PACAP and NGF acts in synergy to induce prolonged activation of ERK1/2. These results indicate for the first time that PACAP induces activation of Rac1 associated with neurite outgrowth and suggest that the synergistic effect of PACAP and NGF on neurite extension is due to enhanced activation of ERK1/2.

Actin Cytoskeleton↗

PubMed2004

Overexpression of pituitary adenylate cyclase-activating polypeptide in islets inhibits hyperinsulinemia and islet hyperplasia in agouti yellow mice.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an intraislet neuropeptide and shares insulinotropic and insulin-sensitizing properties with glucagon-like peptide-1 (GLP-1); however, the pathophysiological significance of PACAP in diabetes remains largely unknown. To assess this, we crossed our recently developed transgenic mice overexpressing PACAP in pancreatic beta-cells (Tg/+), with lethal yellow agouti (KKA(y)) mice (A(y)/+), a genetic model for obesity-diabetes, and examined the metabolic and morphological phenotypes of F(1) animals. Tg/+ mice with the A(y) allele (Tg/+:A(y)/+) developed maturity-onset obesity and diabetes associated with hyperglycemia, hyperlipidemia, and hyperphagia, similar to those of A(y)/+ mice, but hyperinsulinemia was significantly ameliorated in Tg/+:A(y)/+ mice. Although A(y)/+ mice exhibited a marked increase in islet mass resulting from hyperplasia and hypertrophy, this increase was significantly attenuated in Tg/+:A(y)/+ mice. Size frequency distribution analysis revealed that the very large islets comprising one-fourth of islets of A(y)/+ mice were selectively reduced in Tg/+:A(y)/+ mice. Because functional defects have been demonstrated in the large islets of obese animal models, together these findings suggest that PACAP regulates hyperinsulinemia and the abnormal increase in islet mass that occurs during the diabetic process.

Animals↗

PubMed2004

Astrocyte apoptosis: implications for neuroprotection.

Astrocytes, the most abundant glial cell types in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity. Accordingly, impairment in these astrocyte functions can critically influence neuronal survival. Recent studies show that astrocyte apoptosis may contribute to pathogenesis of many acute and chronic neurodegenerative disorders, such as cerebral ischemia, Alzheimer's disease and Parkinson's disease. We found that incubation of cultured rat astrocytes in a Ca(2+)-containing medium after exposure to a Ca(2+)-free medium causes an increase in intracellular Ca(2+) concentration followed by apoptosis, and that NF-kappa B, reactive oxygen species, and enzymes such as calpain, xanthine oxidase, calcineurin and caspase-3 are involved in reperfusion-induced apoptosis. Furthermore, we demonstrated that heat shock protein, mitogen-activated protein/extracellular signal-regulated kinase, phosphatidylinositol-3 kinase and cyclic GMP phosphodiesterase are target molecules for anti-apoptotic drugs. This review summarizes (1) astrocytic functions in neuroprotection, (2) current evidence of astrocyte apoptosis in both in vitro and in vivo studies including its molecular pathways such as Ca(2+) overload, oxidative stress, NF-kappa B activation, mitochondrial dysfunction, endoplasmic reticulum stress, and protease activation, and (3) several drugs preventing astrocyte apoptosis. As a whole, this article provides new insights into the potential role of astrocytes as targets for neuroprotection. In addition, the advance in the knowledge of molecular mechanisms of astrocyte apoptosis may lead to the development of novel therapeutic strategies for neurodegenerative disorders.

Animals↗

PubMed2004

Up-regulation of Na(+)-Ca2+ exchange activity by interferon-gamma in cultured rat microglia.

The Na(+)-Ca2+ exchanger (NCX) plays a role in regulating intracellular Ca2+ concentration, but little is known about NCX in microglia. We examined mRNA expression of NCX isoforms in cultured rat microglia and the effect of interferon-gamma (IFN-gamma) on NCX activity. RT-PCR showed that all of the known NCX isoforms, NCX1-3, are expressed in cultured microglia. Ouabain and monensin increased 45Ca2+ uptake and intracellular Ca2+ concentration in microglia, suggesting the presence of NCX activity in the reverse mode. Treatment with IFN-gamma (100 U/mL) caused a biphasic increase in NCX activity. The transient increase in NCX activity by IFN-gamma for 1 h was blocked by the protein kinase C (PKC) inhibitors, staurosporine and GF109203X, and the tyrosine kinase inhibitor, herbimycin A. The delayed increase in NCX activity by IFN-gamma for 24 h was blocked by the protein synthesis inhibitor cycloheximide and actinomycin D. Treatment with IFN-gamma for 24 h increased NCX mRNA and protein levels. The increase in NCX activity and NCX protein by IFN-gamma for 24 h was blocked by staurosporine, GF109203X, herbimycin A and the extracellular signal-regulated kinase inhibitor, PD98059. These findings suggest that NCX is up-regulated by IFN-gamma in a biphasic manner in microglia. Moreover, PKC and tyrosine kinase are involved in the up-regulation of NCX and the extracellular signal-regulated protein kinase is also involved in the delayed increase in NCX activity.

Animals↗

PubMed2004

Focal adhesion kinase mediates endothelin-induced cyclin D3 expression in rat cultured astrocytes.

Focal adhesion kinase (FAK), a non-receptor type tyrosine kinase, is involved in the G1/S phase cell cycle transition of astrocytes induced by endothelin-1 (ET-1). In this study, the roles of FAK in the expression of cyclin D1 or D3, which are pivotal in G1/S phase transition, were examined in cultured astrocytes. Accompanied with increases in bromodeoxyuridine (BrdU) incorporation, ET-1 (100 nm) increased the numbers of cyclin D1- and D3-positive astrocytes. PD98059 (a MEK inhibitor) and PP-2 (a Src kinase inhibitor) inhibited ET-induced cyclin D1 expression and BrdU incorporation without affecting cyclin D3 expression. In contrast, cytochalasin D, lovastatin (a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor) and Y-27632 (a rho-kinase inhibitor) prevented both cyclin D3 expression and BrdU incorporation. FAK phosphorylation by ET-1 was inhibited by cytochalasin D, lovastatin and Y-27632, but not by PD98059 or PP-2. Transfection with wild-type FAK increased expression of cyclin D3 in astrocytes, while that of cyclin D1 was not affected. Dominant-negative FAK mutants prevented an ET-induced increase in cyclin D3 expression, but not D1. These results suggest that activation of FAK causes cyclin D3 expression in cultured astrocytes, which would underlie the FAK-mediated astrocytic G1/S phase transition by ET-1.

Animals↗

PubMed2004

Effects of SEA0400 on mutant NCX1.1 Na+-Ca2+ exchangers with altered ionic regulation.

SEA0400 (SEA) blocks cardiac and neuronal Na+-Ca2+ exchange with the highest affinity of any known inhibitor, yet very little is known about its molecular mechanism of action. Previous data from our lab suggested that SEA stabilizes or modulates the transition of NCX1.1 exchangers into a Na+i-dependent (I1) inactive state. To test this hypothesis, we examined the effects of SEA on mutant exchangers with altered ionic regulatory properties. With mutants where Na+i-dependent inactivation is absent, the effects of SEA were greatly reduced. Conversely, with mutants displaying accelerated Na+i-dependent inactivation, block of NCX1.1 by SEA was either enhanced or unchanged, depending upon the phenotype of the particular mutation. With mutant exchangers where Ca2+i-dependent (I2) inactivation was suppressed, block of exchange currents by SEA was similar to that observed for wild-type NCX1.1. These data strongly support the involvement of I1 inactivation in the inhibitory mechanism of NCX1.1 by SEA, whereas I2 inactivation does not seem to serve an important role. The involvement of processes regulated by intracellular Na+ in the inhibitory mechanism of SEA may prove to be particularly important when considering the potential cardioprotective effects of this agent.

Aniline Compounds↗

PubMed2004

Susceptibilities to and mechanisms of excitotoxic cell death of adult mouse inner retinal neurons in dissociated culture.

PURPOSE: To explore the susceptibilities of adult retinal neurons in dissociated culture to treatments with excitotoxic agonists and the mechanisms of the resultant retinal cell death. METHODS: C57B6 mice were used. Retinas were removed, dissociated, plated on a polylysine/laminin substrate, and maintained in vitro for 5 to 7 days. Excitotoxic agonists (glutamate, N-methyl-D-aspartate [NMDA], or kainic acid [KA]) were added for 30 minutes or 24 hours, sometimes in the presence of modified extracellular ion concentrations or potential blocking agents. The next day, cells were fixed and immunocytochemically stained to identify ganglion and amacrine cells. Surviving cells were counted. RESULTS: Ganglion cells from adult mouse retinas were much less susceptible to excitotoxic death than those prepared from neonatal retinas. Adult amacrine cells were killed by KA, NMDA, or glutamate. Experiments with selective blockers demonstrated that KA killed through AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, whereas NMDA and glutamate exerted toxicity through a combination of AMPA and NMDA receptors. The KA-induced death of amacrine cells was not mediated by chloride ions. Removal of extracellular sodium, however, completely prevented the amacrine cell death, and removal of extracellular calcium prevented approximately 70% of the death. The path of calcium entry was investigated. Experiments with selective blockers indicated that the lethal calcium entry was via reverse operation of a sodium-calcium exchanger. CONCLUSIONS: There is a profound developmental regulation in the sensitivity of retina ganglion cells to excitotoxic insults. Excessive intracellular sodium and calcium are the proximal causes of amacrine cell death. The pathologic calcium entry is dependent on the sodium overload, which then drives a sodium-calcium exchanger to take up calcium.

Amacrine Cells↗

PubMed2004

The pituitary adenylate cyclase-activating polypeptide is a physiological inhibitor of platelet activation.

The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide of the vasoactive intestinal peptide/secretin/glucagon superfamily. Studies in two related patients with a partial trisomy 18p revealed three copies of the PACAP gene and elevated PACAP concentrations in plasma. The patients suffer from severe mental retardation and have a bleeding tendency with mild thrombocytopenia, and their fibroblasts show increased PACAP mRNA levels. The PACAP receptor (vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor 1 [VPAC1]) in platelets and fibroblasts is coupled to adenylyl cyclase activation. Accordingly, we found increased basal cAMP levels in patients' platelets and fibroblasts, providing a basis for the reduced platelet aggregation in these patients. Megakaryocyte-specific transgenic overexpression of PACAP in mice correspondingly increased PACAP release from platelets, reduced platelet activation, and prolonged the tail bleeding time. In contrast, the PACAP antagonist PACAP(6-38) or a monoclonal PACAP antibody enhanced the collagen-induced aggregation of normal human platelets, and in PACAP knockout mice, an increased platelet sensitivity toward collagen was found. Thus, we found that PACAP modulates platelet function and demonstrated what we believe to be the first hemostatic defect associated with PACAP overexpression; our study suggests the therapeutic potential to manage arterial thrombosis or bleeding by administration of PACAP mimetics or inhibitors, respectively.

Adenylyl Cyclases↗

PubMed2004

[Transgenic mice overexpressing PACAP in pancreatic beta-cells: acute and chronic effects on insulin and glucose homeostasis].

PACAP belongs to the vasoactive intestinal polypeptide (VIP)/secretin/glucagon superfamily, which also includes glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). PACAP shares an insulinotropic property with the latter two peptides; for instance, it stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. However, the pathophysiological significance of PACAP in diabetes remains largely unknown, for several reasons, including a lack of low-molecular weight PACAP ligands and a lack of suitable animal models. As an approach to understanding PACAP's pancreatic function in vivo, we have recently generated transgenic mice overexpressing PACAP in islet beta cells under the control of human insulin promoter (Tg mice). As a consequence, it has been demonstrated that in addition to stimulating insulin secretion, PACAP has long-term effects on pancreatic endocrine cells, including proliferation of beta cells during streptozotocin-induced diabetes development as well as aging. These observations provide additional information to support the possibility that drugs associated with PACAP-signaling pathways might be of therapeutic value for the treatment of diabetes. In this review, we briefly summarize these previous studies using Tg mice and also focus on the physiological and pathophysiological roles mediated by PACAP during diabetes development.

Animals↗

PubMed2004

[Altered higher brain function in PACAP-knockout mice].

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that functions as not only a neurotransmitter/neuromodulator but also a neurotrophic factor. To assess the roles of endogenous PACAP, several groups including ours have independently produced mice with targeted mutations in the PACAP gene. The phenotypes of the mutant mice both confirm and extend our knowledge of the physiological roles of PACAP in the central nervous system as well as many peripheral organs. In this review, we briefly summarize the roles of PACAP in higher brain function, which have been proposed by the studies using the mutant mice as well as histological and pharmacological approaches.

Animals↗

PubMed2004

T-588, a cognitive enhancer, protects against sodium nitroprusside-induced toxicity in cultured astrocytes.

The effects of (1R)-1-benzo[b]thiophen-5-yl-2-[2-(diethylamino)ethoxy]ethan-1-ol hydrochloride (T-588), a cognitive enhancer, on sodium nitroprusside (SNP)-induced cytotoxicity were examined in cultured rat astrocytes. Treatment with 100 microM SNP for 72 h decreased cell viability and mitochondrial function assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenil tetrazolium bromide (MTT) reduction activity, mitochondrial transmembrane potential, and intracellular ATP level. T-588 at 100 microM prevented SNP-induced mitochondrial dysfunction and cell injury. Furthermore, T-588 increased MTT reduction activity without affecting cell proliferation in astrocytes. These results suggest that T-588 has a protective effect against SNP-mediated toxicity via improvement of mitochondrial dysfunction in astrocytes.

Animals↗

PubMed2003

Functional roles of the neuropeptide PACAP in brain and pancreas.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide implicated in a broad variety of physiological processes. To assess PACAP's function in vivo, we recently generated PACAP knockout mice (PACAP(-/-)) and transgenic mice overexpressing PACAP specifically in the pancreas (PACAP-Tg). In PACAP(-/-) mice, we have demonstrated a marked phenotypic changes including a high early mortality rate, increased novelty-seeking behavior and abnormal explosive jumping in a novel environment, as well as reduced female fertility. In this paper, we reevaluated these phenotypes in terms of the genetic background of the mice. Genetic background appears to modulate critically the magnitude but not the general nature of the PACAP-null phenotype. In PACAP-Tg mice, we have recently demonstrated that enhanced glucose-induced insulin secretion with normal glucose tolerance, amelioration of streptozotocin-induced diabetes with increased beta-cell proliferation, and a trend towards an increase in total islet mass with age. Here we show that PACAP(-/-) mice exhibit significantly impaired glucose-induced insulin secretion but still have normal glucose tolerance. These observations suggest that PACAP may play important roles in and beyond the regulation of insulin release. Taken together, the mutant phenotypes revealed both expected and unexpected roles of PACAP in the brain and pancreatic functions.

Animals↗

PubMed2003

Molecular determinants of Na+/Ca2+ exchange (NCX1) inhibition by SEA0400.

SEA0400 is a potent and selective Na(+)/Ca(2+) exchanger (NCX) inhibitor. We evaluated the inhibitory effects of SEA0400 on Na(+)(i)-dependent (45)Ca(2+) uptake and whole-cell Na(+)/Ca(2+) exchange currents in NCX-transfected fibroblasts. SEA0400 preferentially inhibited (45)Ca(2+) uptake by NCX1 compared with inhibitions by NCX2, NCX3, and NCKX2. SEA0400 also selectively blocked outward exchange currents from NCX1 transfectants. We searched for regions that may form the SEA0400 receptor in the NCX1 molecule by NCX1/NCX3 chimeric analysis. The results suggest that the first intracellular loop and the fifth transmembrane segment are mostly responsible for the differential drug responses between NCX1 and NCX3. Further site-directed mutagenesis revealed that multiple mutations at Phe-213 markedly reduced sensitivity to SEA0400 without affecting that to KB-R7943. We also found that Gly-833-to-Cys mutation (within the alpha-2 repeat) greatly reduced the inhibition by SEA0400, but unexpectedly the NCX1 chimera with an alpha-2 repeat from NCKX2 possessed normal drug sensitivity. In addition, exchangers with mutated exchanger inhibitory peptide regions, which display either undetectable or accelerated Na(+)-dependent inactivation, had a markedly reduced sensitivity or hypersensitivity to SEA0400, respectively. To verify the efficacy of the NCX inhibitor, we examined the renoprotective effect of SEA0400 in a hypoxic injury model using porcine renal tubular cells. SEA0400 protected against hypoxia/reoxygenation-induced cell damage in tubular cells expressing wild-type NCX1 but not in cells expressing SEA0400-insensitive mutants. These results suggest that Phe-213, Gly-833, and residues that eliminate Na(+)-dependent inactivation are critical determinants for the inhibition by SEA0400, and their mutants are very useful for checking the pharmacological importance of NCX inhibition by SEA0400.

Alternative Splicing↗

PubMed2003

Possible involvement of a cyclic AMP-dependent mechanism in PACAP-induced proliferation and ERK activation in astrocytes.

In cultured astrocytes, PACAP activates extracellular signal-regulated kinase (ERK) and induces cell proliferation at picomolar concentrations. Here, we examined the role of cyclic AMP signaling underlying the effects of PACAP. PACAP38 induced accumulation of cyclic AMP in astrocytes at concentrations as low as 10(-12)M. PACAP38 (10(-12)-10(-9)M)-stimulated cell proliferation was completely abolished by the cyclic AMP antagonist Rp-cAMP, whereas the protein kinase A (PKA) inhibitor H89 had no effect. This PACAP38-mediated effect was also abolished by the ERK kinase inhibitor PD98059, suggesting the involvement of ERK in PACAP-induced proliferation. PACAP38 (10(-12)M)-stimulated phosphorylation of ERK lasted for at least 60 min. This effect was completely abolished by Rp-cAMP but not by H89. Dibutyryl cyclic AMP maximally stimulated the incorporation of thymidine and activation of ERK at 10(-10)M. These results suggest that PACAP-mediated stimulation of ERK activity and proliferation of astrocytes may involve a cyclic AMP-dependent, but PKA-independent, pathway.

Animals↗

PubMed2003

Impaired long-term potentiation in vivo in the dentate gyrus of pituitary adenylate cyclase-activating polypeptide (PACAP) or PACAP type 1 receptor-mutant mice.

The present study was conducted to clarify a role of pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP type 1 receptor (PAC1R) in learning and memory function. We demonstrated long-term potentiation (LTP) in vivo in the dentate gyrus of PAC1R exon 2-deficient (PAC1R-/-) mice and heterozygous PACAP-deficient (PACAP+/-) mice using extracellular recording techniques. We used two paradigms of tetanic stimulation, suprathreshold and at threshold tetanus, which both induced LTP in vivo in PAC1R-/- and PACAP+/- mice. However, the population spike of 'at threshold' but not 'suprathreshold' LTP decreased significantly in PAC1R-/- and PACAP+/- mice. At threshold LTP of PACAP+/- mice was impaired greater than the one of PAC1R-/- mice. Thus, both PACAP and PAC1R could contribute to the establishment of LTP in a gene dosage-dependent manner, although PACAP rather than PAC1R might play a pivotal role in learning and memory function.

Action Potentials↗

PubMed2003

Changes in light-induced phase shift of circadian rhythm in mice lacking PACAP.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is one of the neurotransmitters that transfers light signals from the retina to the hypothalamic suprachiasmatic nucleus (SCN) where the master clock of mammalian circadian rhythm locates, and is suggested to be implicated in the mechanism of light-induced phase shift of the circadian clock. Here, we examined changes in the phase shift of circadian rhythm in behavioral activity in mice lacking PACAP (PACAP(-/-)). The phase advance in PACAP(-/-) mice by a light stimulation at late subjective night was significantly attenuated, but the phase delay due to the illumination at the early subjective night slightly diminished. In contrast, the induction of c-Fos in the SCN by the illumination at the early subjective night but not that at the late subjective night was significantly blunted in PACAP(-/-) mice. These data provide new aspects about the roles of PACAP in light-induced phase shift of the circadian clock.

Animals↗

PubMed2003

The 5-HT1A receptor agonist MKC-242 reverses isolation rearing-induced deficits of prepulse inhibition in mice.

RATIONALE: Prepulse inhibition (PPI) of startle provides an operational measure of sensorimotor gating in which a weak stimulus presented prior to a startling stimulus reduces the startle response. PPI deficits observed in schizophrenia patients can be modeled in rats by individual housing from weaning until adulthood. The deficits in PPI produced by isolation rearing can be reversed by antipsychotics. We previously found that (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242), a highly potent 5-HT(1A) receptor agonist, reduced aggressive behavior selectively in isolation-reared mice. OBJECTIVE: This study examines whether isolation rearing of mice produces PPI deficits and whether PPI deficits are attenuated by 5-HT(1A) receptor activation. METHODS: Male ddY mice, 4 weeks old, were housed for more than 6 weeks singly or in groups of five or six. The PPI of the acoustic startle response was measured using SR-LAB systems. RESULTS: The PPI was less in isolation-reared mice than in group-reared mice. Oral administration of MKC-242 at 0.1-0.3 mg/kg reversed PPI deficits in isolation-reared mice, although it did not affect PPI in group-reared mice. MKC-242 did not affect MK-801-induced and apomorphine-induced PPI deficits in group-reared mice. The reversal by MKC-242 of isolation-induced PPI deficits was antagonized by the 5-HT(1A) receptor antagonist WAY100635 at low doses. CONCLUSION: These results suggest that isolation rearing produces deficits in sensorimotor gating in mice that are reversible by activation of 5-HT(1A) receptors, probably somatodendritic 5-HT(1A) autoreceptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2003

Endothelin-1 stimulates glial cell line-derived neurotrophic factor expression in cultured rat astrocytes.

Effects of endothelin-1 (ET-1) on glial cell line-derived neurotrophic factor (GDNF) production in cultured astrocytes were examined. Treatment of cultured astrocytes with ET-1 (100 nM) increased mRNA levels of GDNF in 1-6h. The effect of ET-1 was inhibited by BQ788, an ET(B) receptor antagonist, but not by FR139317, an ET(A) receptor antagonist. ET-1 stimulated release of GDNF into culture medium. Dexamethasone (1 microM) and pyrrolidine dithiocarbamate (PDTC, 100 microM), which inhibit activation of NFkappaB, prevented the increases in GDNF mRNA by H(2)O(2). In contrast, the effect of ET-1 was not affected by dexamethasone and PDTC. The increase of astrocytic GDNF mRNA by ET-1 was inhibited by BAPTA/AM (30 microM) and PD98059 (50 microM), but not by calphostin C, staurosporine, and cyclosporine A. These results suggest that ET-1 stimulated expression of astrocytic GDNF through ET(B) receptor-mediated increases in cytosolic Ca(2+) and ERK activation.

Animals↗