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Biomedical subjects

M Basille

Publications and source records attributed to M Basille.

At least 19 recordsLinked to original sources
PubMed2004

PACAP inhibits delayed rectifier potassium current via a cAMP/PKA transduction pathway: evidence for the involvement of I k in the anti-apoptotic action of PACAP.

Abstract Activation of potassium (K(+)) currents plays a critical role in the control of programmed cell death. Because pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to inhibit the apoptotic cascade in the cerebellar cortex during development, we have investigated the effect of PACAP on K(+) currents in cultured cerebellar granule cells using the patch-clamp technique in the whole-cell configuration. Two types of outward K(+) currents, a transient K(+) current (I(A)) and a delayed rectifier K(+) current (I(K)) were characterized using two different voltage protocols and specific inhibitors of K(+) channels. Application of PACAP induced a reversible reduction of the I(K) amplitude, but did not affect I(A), while the PACAP-related peptide vasoactive intestinal polypeptide had no effect on either types of K(+) currents. Repeated applications of PACAP induced gradual attenuation of the electrophysiological response. In the presence of guanosine 5'-[gammathio]triphosphate (GTPgammaS), PACAP provoked a marked and irreversible I(K) depression, whereas cell dialysis with guanosine 5'-[betathio]diphosphate GDPbetaS totally abolished the effect of PACAP. Pre-treatment of the cells with pertussis toxin did not modify the effect of PACAP on I(K). In contrast, cholera toxin suppressed the PACAP-induced inhibition of I(K). Exposure of granule cells to dibutyryl cyclic adenosine monophosphate (dbcAMP) mimicked the inhibitory effect of PACAP on I(K). Addition of the specific protein kinase A inhibitor H89 in the patch pipette solution prevented the reduction of I(K) induced by both PACAP and dbcAMP. PACAP provoked a sustained increase of the resting membrane potential in cerebellar granule cells cultured either in high or low KCl-containing medium, and this long-term depolarizing effect of PACAP was mimicked by the I(K) specific blocker tetraethylammonium chloride (TEA). In addition, pre-incubation of granule cells with TEA suppressed the effect of PACAP on resting membrane potential. TEA mimicked the neuroprotective effect of PACAP against ethanol-induced apoptotic cell death, and the increase of caspase-3 activity observed after exposure of granule cells to ethanol was also significantly inhibited by TEA. Taken together, the present results demonstrate that, in rat cerebellar granule cells, PACAP reduces the delayed outward rectifier K(+) current by activating a type 1 PACAP (PAC1) receptor coupled to the adenylyl cyclase/protein kinase A pathway through a cholera toxin-sensitive Gs protein. Our data also show that PACAP and TEA induce long-term depolarization of the resting membrane potential, promote cell survival and inhibit caspase-3 activity, suggesting that PACAP-evoked inhibition of I(K) contributes to the anti-apoptotic effect of the peptide on cerebellar granule cells.

4-Aminopyridine↗
PubMed2002

PACAP protects cerebellar granule neurons against oxidative stress-induced apoptosis.

Oxidative stress, resulting from accumulation of reactive oxygen species, plays a critical role in neuronal cell death associated with neurodegenerative diseases and stroke. In the present study, we have investigated the potential neuroprotective effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on oxidative stress-induced apoptosis. Incubation of cerebellar granule cells with PACAP inhibited hydrogen peroxide-evoked cell death in a concentration-dependent manner. The effect of PACAP on granule cell survival was not mimicked by vasoactive intestinal polypeptide and was blocked by the antagonist PACAP6-38. The protective action of PACAP upon hydrogen peroxide-induced neuronal cell death was abolished by the MAP-kinase kinase (MEK) inhibitor U0126 and mimicked by the caspase-3 inhibitor Z-DEVD-FMK. PACAP markedly inhibited hydrogen peroxide-evoked caspase-3 activation and DNA fragmentation. Taken together, these data indicate that PACAP, acting through PACAP receptor type 1, exerts a potent protective effect against neuronal degeneration induced by hydrogen peroxide. The anti-apoptotic effect of PACAP is mediated through the MAP-kinase pathway and can be accounted for by inhibition of caspase-3 activation resulting from oxidative stress.

Animals↗
PubMed2000

The neuroprotective effect of pituitary adenylate cyclase-activating polypeptide on cerebellar granule cells is mediated through inhibition of the CED3-related cysteine protease caspase-3/CPP32.

Caspase-3 knockout mice exhibit thickening of the internal granule cell layer of the cerebellum. Concurrently, it has been shown that intracerebral injection of pituitary adenylate cyclase-activating polypeptide (PACAP) induces a transient increase of the thickness of the cerebellar cortex. In the present study, we have investigated the possible effect of PACAP on caspase activity in cultured cerebellar granule cells from 8-day-old rat. Incubation of granule neurons with PACAP for 24 h promoted cell survival and prevented DNA fragmentation. Exposure of cerebellar granule cells to the specific caspase-3 inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp fluoromethylketone (Z-DEVD-FMK) for 24 h markedly enhanced cell survival and inhibited apoptotic cell death. Time-course studies revealed that PACAP causes a prolonged inhibition of caspase-3 activity without affecting caspase-1. Administration of graded concentrations of PACAP for 3 h induced a dose-dependent inhibition of caspase-3 activity. Incubation of granule cells with both dibutyryl-cAMP (dbcAMP) and phorbol 12-myristate 13-acetate (PMA) mimicked the inhibitory effect of PACAP on caspase-3. Cotreatment of cultured neurons with the protein kinase A inhibitor H89 and the protein kinase C inhibitor chelerythrine abrogated the effect of PACAP on caspase-3 activity. In contrast, the ERK kinase inhibitor U0126 did not affect the action of PACAP on caspase-3 activity. These data demonstrate that PACAP prevents cerebellar granule neurons from apoptotic cell death through a protein kinase A- and protein kinase C-dependent inhibition of caspase-3 activity.

Animals↗
PubMed2000

Comparative distribution of pituitary adenylate cyclase-activating polypeptide (PACAP) binding sites and PACAP receptor mRNAs in the rat brain during development.

The distribution and density of pituitary adenylate cyclase-activating polypeptide (PACAP) binding sites as well as PACAP-specific receptor 1 (PAC1-R), vasoactive intestinal polypeptide/PACAP receptor 1 (VPAC1-R), and VPAC2-R mRNAs have been investigated in the rat brain from embryonic day 14 (E14) to postnatal day 8 (P8). Significant numbers of binding sites for the radioiodinated, 27-amino-acid form of PACAP were detected as early as E14 in the neuroepithelia of the metencephalon and the myelencephalon. From E14 to E21, the density of binding sites in the germinative areas increased by 3- to 5-fold. From birth to P12, the density of binding sites gradually declined in all neuroepithelia except in the external granule cell layer of the cerebellum, where the level of binding sites remained high during the first postnatal weeks. Only low to moderate densities of PACAP binding sites were found in regions other than the germinative areas, with the exception of the internal granule cell layer of the cerebellum, which contained a high density of sites. The localization of PACAP receptor mRNAs was investigated by in situ hybridization using [(35)S] uridine triphosphate-specific riboprobes. The evolution of the distribution of PAC1-R and VPAC1-R mRNAs was very similar to that of PACAP binding sites, the concentration of VPAC1-R mRNA being much lower than that of PAC1-R mRNA. In contrast, intense expression of VPAC2-R mRNA was observed in brain regions other than germinative areas, such as the suprachiasmatic, ventral thalamic, and dorsolateral geniculate nuclei. The discrete localization of PACAP binding sites as well as PAC1-R and VPAC1-R mRNAs in neuroepithelia during embryonic life and postnatal development strongly suggests that PACAP, acting through PAC1-R and/or VPAC1-R, may play a crucial role in the regulation of neurogenesis in the rat brain.

Aging↗
PubMed2000

PACAP acts as a neurotrophic factor during histogenesis of the rat cerebellar cortex.

During development of the rat cerebellum, PAC1 receptors are transiently expressed by neuroblasts of the external granule cell layer (EGL). We have previously shown that PACAP is a potent stimulator of granule cell survival in vitro. In the study reported in this paper, we have investigated the effect of PACAP on the development of the rat cerebellar cortex in vivo. PACAP induces a transient increase in the volume of the cerebellar cortex, with a maximum effect at postnatal day 12, which can be accounted for by an increase in the number of granule cells in the EGL, the molecular layer, and the internal granule cell layer (IGL). The effect of PACAP on the number of granule cells is blocked by the antagonist PACAP(6-38), which, by itself, produces a slight inhibition of the number of granule cells in the IGL. These data indicate that PACAP activates proliferation and/or inhibits programmed cell death of granule cells in the developing rat cerebellum. PACAP also stimulates neuronal migration from the EGL to the IGL. Thus, it appears that PACAP can act in vivo as a neurotrophic factor controlling histogenesis of the cerebellar cortex.

Animals↗
PubMed2000

Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was first isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP formation in anterior pituitary cells. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-glucagon-growth hormone releasing factor-secretin superfamily. The sequence of PACAP has been remarkably well conserved during the evolution from protochordate to mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, and respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide whose activity remains unknown. Two types of PACAP binding sites have been characterized. Type I binding sites exhibit a high affinity for PACAP and a much lower affinity for VIP whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes, the PACAP-specific PAC1 receptor, which is coupled to several transduction systems, and the two PACAP/VIP-indifferent VPAC1 and VPAC2 receptors, which are primarily coupled to adenylyl cyclase. PAC1 receptors are particularly abundant in the brain and pituitary and adrenal glands whereas VPAC receptors are expressed mainly in the lung, liver, and testis. The wide distribution of PACAP and PACAP receptors has led to an explosion of studies aimed at determining the pharmacological effects and biological functions of the peptide. This report reviews the current knowledge concerning the multiple actions of PACAP in the central nervous system and in various peripheral organs including the endocrine glands, the airways, and the cardiovascular and immune systems, as well as the different effects of PACAP on a number of tumor cell types.

Amino Acid Sequence↗
PubMed1999

Neurotrophic activity of pituitary adenylate cyclase-activating polypeptide on rat cerebellar cortex during development.

High concentrations of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are present in the external granule cell layer of the rat cerebellum during postnatal development. In vitro studies have shown that PACAP promotes cell survival and neurite outgrowth on immature cerebellar granule cells in primary culture. In the present study, we have investigated the effect of PACAP on the development of the cerebellar cortex of 8-day-old rats. Incubation of cultured granule cells for 12 or 18 h with PACAP provoked a significant increase in the rate of incorporation of [(3)H]thymidine in cultured granule cells, suggesting that PACAP could stimulate the proliferation of granule cells. After 96 h of treatment, in vivo administration of PACAP provoked a transient increase in the number of granule cells in the molecular layer and in the internal granule cell layer. In contrast, PACAP did not affect the number of Purkinje cells. The augmentation of the number of granule cells evoked by PACAP was significantly inhibited by the PACAP receptor antagonist PACAP(6-38). Administration of PACAP also caused a significant increase in the volume of the cerebellar cortex. The present study provides evidence that PACAP can act in vivo as a trophic factor during rat brain development. Our data indicate that PACAP increases proliferation and/or inhibits programmed cell death of granule cells, as well as stimulating neuronal migration from the external granule cell layer toward the internal granule cell layer.

Aging↗
PubMed1999

Long-term enhancement of REM sleep by the pituitary adenylyl cyclase-activating polypeptide (PACAP) in the pontine reticular formation of the rat.

In rats, rapid eye movement (REM) sleep can be elicited by microinjection of vasoactive intestinal polypeptide (VIP) into the oral pontine reticular nucleus (PnO). In the present study, we investigated whether this area could also be a REM-promoting target for a peptide closely related to VIP: the pituitary adenylyl cyclase-activating polypeptide (PACAP). When administered into the posterior part of the PnO, but not in nearby areas, of freely moving chronically implanted rats, PACAP-27 and PACAP-38 (0.3 and 3 pmol) induced a marked enhancement (60-85% over baseline) of REM sleep for 8 h that could be prevented by prior infusion of the antagonist PACAP-(6-27) (3 pmol) into the same site. Moreover, injections of PACAP into the centre of the posterior PnO resulted in REM sleep enhancement which could last for up to 11 consecutive days. Quantitative autoradiography using [125I]PACAP-27 revealed the presence in the PnO of specific binding sites with high affinity for PACAP-27 and PACAP-38 (IC50 = 2.4 and 3.2 nM, respectively), but very low affinity for VIP (IC50 > 1 microM). These data suggest that PACAP within the PnO may play a key role in REM sleep regulation, and provide evidence for long-term (several days) mechanisms involved in such a control. PAC1 receptors which have a much higher affinity for PACAP than for VIP might mediate this long-term action of PACAP on REM sleep.

Animals↗
PubMed1998

The neurotrophic activity of PACAP on rat cerebellar granule cells is associated with activation of the protein kinase A pathway and c-fos gene expression.

In vitro studies have shown that PACAP promotes cell survival and neurite outgrowth in immature cerebellar granule cells. In the present study, we have examined the transduction pathways involved in the neurotrophic activity of PACAP. Incubation of cultured granule cells with graded concentrations of PACAP produced a dose-dependent increase in c-fos mRNA level. The effects of PACAP on c-fos gene expression and granule cell survival were both mimicked by dbcAMP but not by PMA. The maximum effect of PACAP on c-fos gene expression was observed after 1 h of treatment. Similar effects of the peptide on granule cell survival were observed whether the cells were continuously incubated with PACAP for 48 h or only exposed to PACAP during 1 h. The PKA inhibitor H89 significantly reduced the effect of PACAP on c-fos mRNA level, whereas the specific PKC inhibitor chelerytrine had no effect. These data indicate that the action of PACAP on cerebellar granule cell survival and c-fos gene expression are both mediated through the adenylyl cyclase/PKA pathway.

Animals↗
PubMed1998

Pituitary adenylate cyclase-activating polypeptide stimulates both c-fos gene expression and cell survival in rat cerebellar granule neurons through activation of the protein kinase A pathway.

A high density of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors coupled to both adenylyl cyclase and phospholipase C is found in the external granule cell layer of the rat cerebellum during postnatal development. It has recently been reported that synthetic PACAP promotes cell survival and neurite outgrowth in immature granule cells. In the present study, we have investigated the transduction pathways that mediate the neurotrophic activity of PACAP in cultured granule cells from eight-day-old rat cerebellum. The effect of PACAP on cell survival was mimicked by dibutyryladenosine 3',5'-cyclic-monophosphate but not phorbol 12-myristate 13-acetate suggesting that only the adenylyl cyclase pathway is involved in the neurotrophic activity of PACAP. PACAP also induced a transient increase in c-fos messenger RNA level. The ability of PACAP to stimulate c-fos gene expression was mimicked by dibutyryladenosine 3',5'-cyclic-monophosphate but not phorbol 12-myristate 13-acetate. Similar effects of PACAP on granule cell survival were observed whether the cells were continuously incubated with PACAP for 48 h or only exposed to PACAP during 1 h. The protein kinase A inhibitor H89 significantly reduced the effect of PACAP on c-fos messenger RNA level whereas the specific protein kinase C inhibitor chelerythrine did not modify c-fos gene expression. These data indicate that the action of PACAP on cerebellar granule cell survival and c-fos gene expression are both mediated through the adenylyl cyclase/protein kinase A pathway. The observation that a short-term stimulation by PACAP can be converted into a long-lasting response indicates that the effect of the peptide on cell survival must involve immediate-early gene activation. The fact that a brief exposure to PACAP causes both c-fos gene expression and promotes cell survival strongly suggests that c-fos is involved in the trophic effect of PACAP on immature cerebellar granule cells.

Adenylyl Cyclases↗
PubMed1998

Pharmacological, molecular and functional characterization of vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating polypeptide receptors in the rat pineal gland.

Melatonin secretion from the mammalian pineal gland is strongly stimulated by noradrenaline and also by vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Three types of receptors for VIP and PACAP have been characterized so far: VIP1/PACAP receptors and VIP2/PACAP receptors, which possess similar high affinities for VIP and PACAP, and PACAP1 receptors which exhibit a 100-1000-fold higher affinity for PACAP. The aim of the present study was to characterize the receptor subtype(s) mediating the stimulatory effects of VIP and PACAP on melatonin synthesis in the rat pineal gland. Autoradiographic studies showed that PACAP and VIP were equally potent in displacing binding of radioiodinated PACAP27 from pineal sections. Amplification of pineal complementary DNAs by polymerase chain reaction using specific primers for the different receptor subtypes revealed that all three receptor messenger RNAs are expressed and that VIP1/PACAP receptor messenger RNA was predominant over VIP2/PACAP receptor messenger RNA. In vitro, VIP and PACAP stimulated melatonin synthesis with similar high potency and the effect of the two peptides were not additive. The selective VIP1/PACAP receptor agonists [R16]chicken secretin (1-25) and [K15, R16, L27]VIP(1-7)/growth hormone releasing factor(8-27) were significantly more potent than the selective VIP2/PACAP receptor agonist RO 25-1553 in stimulating melatonin secretion. The stimulatory effects of VIP and PACAP were similarly inhibited by the VIP1/PACAP antagonist [acetyl-His1, D-Phe2, K15, R16, L27]VIP(3-7)/growth hormone releasing factor(8-27). These data strongly suggest that VIP and PACAP exert a stimulatory effect on melatonin synthesis mainly through activation of a pineal VIP1/PACAP receptor subtype.

Adenylyl Cyclases↗
PubMed1998

[Pituitary adenylate cyclase-activating polypeptide].

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been originally isolated from the sheep hypothalamus on the basis of its ability to stimulate cAMP formation in anterior pituitary cells. Post-translational processing of the PACAP precursor generates two biologically active molecular forms, PACAP38 and PACAP27, and a novel peptide called PACAP-related peptide whose activity remains unknown. The primary structure of PACAP has been remarkably conserved during evolution, from protochordates to mammals, suggesting that the peptide exerts important activities throughout the vertebrate phylum. The sequence of PACAP27 exhibits substantial similarities with those of vasoactive intestinal polypeptide (VIP), glucagon and secretin. The gene encoding the PACAP precursor is widely expressed in the brain and in various peripheral organs, notably in endocrine glands, the gastro-intestinal and uro-genital tracts and the respiratory system. In vivo and in vitro studies have shown that PACAP exerts multiple activities as a hormone, neurohormone, neurotransmitter or trophic factor. For instance, PACAP triggers the release of insulin and glucagon, activates steroidogenesis in the adrenal gland and gonads, and stimulates the secretion of most hypophysial cells. PACAP exerts a potent relaxant activity on smooth muscle fibers in blood vessels, lung and gut. In the brain, PACAP stimulates the electrical activity of various populations of neurons and increases tyrosine hydroxylase gene expression. Recent studies have shown that PACAP exerts a trophic activity during ontogenesis, notably in the adrenal medulla and in the central nervous system. The biological effects of PACAP are mediated through three distinct receptor subtypes which exhibit differential affinities for PACAP and VIP. The PAC1 receptor, which shows high selectivity for PACAP, is coupled to several transduction systems. In contrast, VPAC1 and VPAC2, which bind with the same affinity PACAP and VIP, are mainly coupled to the adenylyl cyclase pathway. The bronchodilatator and vasorelaxant effects of PACAP, as well as the antiproliferative and neuroprotective actions of the peptide, make it a valuable target for new drug development.

Adenylyl Cyclases↗
PubMed1997

Pituitary adenylate cyclase-activating polypeptide promotes cell survival and neurite outgrowth in rat cerebellar neuroblasts.

High concentrations of pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors have been detected in the rat cerebellum during ontogenesis. In particular, PACAP receptors are actively expressed in immature granule cells, suggesting that PACAP may act as a neurotrophic factor in the developing rat cerebellum. In the present study, we have investigated the effect of PACAP on cell survival and neurite outgrowth in cultured immature cerebellar granule cells. In control conditions, cultured granule cells undergo programmed cell death. Exposure of cultured cells to PACAP for 24 and 48 h provoked a significant increase in the number of living cells. The effect of PACAP on cell survival was inhibited by the PACAP antagonist PACAP(6-38). Vasoactive intestinal polypeptide was approximately 1000 times less potent than PACAP in promoting cell survival. PACAP also induced a significant increase in the number of processes and in the cumulated length of neurites borne by cultured neuroblasts. The present results demonstrate that PACAP promotes cell survival and neurite outgrowth in cultured immature granule cells. Since PACAP and its receptors are expressed in situ in the rat cerebellar cortex, these data strongly suggest that PACAP plays a physiological role in the survival and differentiation of cerebellar granule cells.

Animals↗
PubMed1995

Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates adenylyl cyclase and phospholipase C activity in rat cerebellar neuroblasts.

The presence of receptors for the novel neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been recently demonstrated in the external granule cell layer of the cerebellum, a germinative matrix that generates the majority of cerebellar interneurons. In the present study, we have taken advantage of the possibility of obtaining a culture preparation that is greatly enriched in immature cerebellar granule cells to investigate the effect of PACAP on the adenylyl cyclase and phospholipase C transduction pathways. The two molecular forms of PACAP, i.e., 27-(PACAP27) and 38-(PACAP38) amino-acid forms of PACAP, induced a dose-dependent stimulation of cyclic AMP production in granule cells. The potencies of PACAP27 and PACAP38 were similar (ED50 = 0.12 +/- 0.01 and 0.23 +/- 0.07 nM, respectively), whereas vasoactive intestinal polypeptide (VIP) was approximately 100 times less potent. PACAP27 and PACAP38 also induced a dose-dependent stimulation of polyphosphoinositide breakdown (ED50 = 19.1 +/- 6.3 and 13.4 +/- 6.0 nM, respectively), whereas VIP had no effect on polyphosphoinositide metabolism. The effect of PACAP38 on inositol phosphate formation was significantly reduced by U-73122 and by pertussis toxin, indicating that activation of PACAP receptors causes stimulation of a phospholipase C through a pertussis toxin-sensitive G protein. In contrast, forskolin and dibutyryl cyclic AMP did not affect PACAP-induced stimulation of inositol phosphates. Taken together, the present results demonstrate that PACAP stimulates independently the adenylyl cyclase and the phospholipase C transduction pathways in immature cerebellar granule cells. These data favor the concept that PACAP may play important roles in the control of proliferation and/or differentiation of cerebellar neuroblasts.

Adenylate Cyclase Toxin↗
PubMed1994

Ontogeny of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in the rat cerebellum: a quantitative autoradiographic study.

Pituitary adenylate cyclase-activating polypeptide and PACAP receptors are both present in the rat cerebellar cortex, suggesting that PACAP may play an important role in the cerebellum. In the present study, the variation of the concentration of PACAP binding sites in the rat cerebellum was investigated during postnatal development by means of quantitative autoradiography, using [125I]PACAP27 as a radioligand. In the external granule cell layer and the medulla, the density of PACAP binding sites was high at birth, markedly decreased from postnatal day 8 (P8) to P25 and finally vanished at the end of the third postnatal week. In the internal granule cell layer and molecular layer, PACAP binding sites were first detected at P8. In the internal granule cell layer, the density of binding sites slightly decreased during development but remained elevated in adults. Conversely, in the molecular layer, PACAP binding sites rapidly decreased during the second and third postnatal weeks and virtually disappeared after P25. In all four layers of the cerebellar cortex, the autoradiographic labeling was displaced by PACAP27 (IC50 close to 10(-8) M), but was not affected by VIP. No significant changes in IC50 and Hill coefficient were noticed in the various layers throughout development. The present study shows that all four layers of the cerebellar cortex express PACAP binding sites during development. The evolution of the receptor concentration exhibited differential profiles in the various layers but the specificity characteristics of the recognition sites were identical in all four structures.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Somatostatin and pituitary adenylate cyclase-activating polypeptide (PACAP): two neuropeptides potentially involved in the development of the rat cerebellum.

Somatostatin and pituitary adenylate cyclase-activating polypeptide (PACAP) have been originally isolated from the ovine hypothalamus on the basis of their hypophysiotropic activities. There is now evidence that somatostatin and PACAP may play a role in the development of the central nervous system, particularly in the cerebellum. High concentrations of somatostatin and somatostatin receptors have been detected in the rat cerebellum during the first two postnatal weeks. Somatostatin binding sites are associated with a germinative matrix, the external granule cell layer, which generates the majority of the interneurons of the cerebellum. By using immature granule cells in primary culture, we could demonstrate that somatostatin binding sites are actually expressed by neuroblasts and correspond to authentic receptors negatively coupled to adenylate cyclase. Concurrently, studies on the distribution of PACAP receptors in the immature rat cerebellum showed the presence of a high concentration of binding sites in the external granule cell layer during the first two postnatal weeks. Pharmacological characterization of these binding sites showed that they correspond to type I PACAP receptors positively coupled to adenylate cyclase. The concomitant and transient expression of somatostatin and PACAP receptors by cerebellar neuroblasts in the external granule cell layer suggests that the two neuropeptides may be involved in the regulation of multiplication, migration and/or differentiation of neuroblasts. This hypothesis is also supported by the actions of somatostatin and PACAP on various transduction systems. In particular, the opposite effects of the two neuropeptides on adenylate cyclase activity suggest that somatostatin and PACAP may exert antagonistic actions.

Animals↗