Function of PACAP in the Central Nervous System

Gonzalez, Bruno J.; Vaudry, David; Basille, M.; Rousselle, Cécile; Falluel-Morel, A.; Vaudry, Hubert

doi:10.1007/978-1-4615-0243-2_6

Cited by 3 publications

(4 citation statements)

References 168 publications

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“…In relation to peptides, Said and Mutt in 1970 reported, for the first time, to the scientific community, the presence of VIP in lung, that was later isolated from small intestine, 4 in an article entitled with the premonitory title of “Polypeptide with broad biological activity: isolation from small intestine.” Twenty years later, in 1989 PACAP was isolated from ovine hypothalamic extracts and it has been described as two amidated forms: PACAP‐27 and PACAP‐38 5 . VIP and PACAP were found widely distributed in the organism as neuroendocrine modulators 6–10 . Both peptides were also, more recently, assigned to the immune system, exerting very novel and interesting functions on innate and acquired immunity.…”

Section: Vip–pacap Framework In Immunitymentioning

confidence: 99%

VIP–PACAP System in Immunity

Gomariz

2006

Annals of the New York Academy of Sciences

105

110

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Our research about VIP/PACAP and the immune system goes back to 1990 when our group described the expression of VIP on lymphocytes for the first time. Since this year, using three models of disease, septic shock, rheumathoid arthritis, and Crohn's disease, we are trying to contribute with new pieces to the puzzle of immunity to approach the use of VIP/PACAP system as a therapeutic agent. In 1999 we established that the first step in the beneficial effect of the VIP/PACAP system exerts consists in its potent anti-inflammatory action. Thus, VIP and PACAP inhibit the expression and release of proinflammatory cytokines and chemokines, and enhance the production of the anti-inflammatory factors. These effects were reported both in vitro and in vivo, are mediated by the presence of PAC1, VPAC1, and VPAC2 receptors, in the three models of diseases used. The next step was that the system favors Th2 responses versus Th1 contributing to the remission of illness as rheumatoid arthritis or Crohn's disease by blocking the autoimmune component of these diseases. Because it appears that inflammatory processes requires more than blockade of a single mediator, new therapies blocking several components of both the infection- and the autoimmunity-induced inflammation cascades should be an interesting focus of attention. In this sense, at present we are trying to dissect new aspects of the potential therapeutic of the VIP/PACAP system in the control of CC and CXC chemokine and their receptors, coagulation factors, adhesion molecules, acute phase proteins, and osteoclastogenesis mediators as well as in the modulation of the expression of Toll-like receptors. Our more recent data open a hopeful door for the therapeutic use of VIP/PACAP in humans.

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Section: Vip–pacap Framework In Immunitymentioning

confidence: 99%

VIP–PACAP System in Immunity

Gomariz

2006

Annals of the New York Academy of Sciences

105

110

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“…The cerebellum is one of the brain areas that is most sensitive to ethanol during development, with loss of both Purkinje neurons 3 and granule cells 4 . Pituitary adenylate cyclase‐activating polypeptide (PACAP) and its receptors are actively expressed in the rat cerebellar cortex during postnatal development 5–7 . In particular, high levels of the PACAP‐specific receptor PAC1‐R are found in the external granule cell layer, a germinative matrix that gives rise to cerebellar interneurons 8 .…”

Section: Introductionmentioning

confidence: 99%

“…4 Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are actively expressed in the rat cerebellar cortex during postnatal development. [5][6][7] In particular, high levels of the PACAP-specific receptor PAC1-R are found in the external granule cell layer, a germinative matrix that gives rise to cerebellar interneurons. 8 In vitro studies have shown that incubation of cultured cerebellar granule cells with PACAP promotes cell survival and stimulates neurite outgrowth.…”

Section: Introductionmentioning

confidence: 99%

The Delayed Rectifier Channel Current I_K Plays a Key Role in the Control of Programmed Cell Death by PACAP and Ethanol in Cerebellar Granule Neurons

Castel

Vaudry

Mei

et al. 2006

Annals of the New York Academy of Sciences

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Alcohol exposure during development causes severe brain malformations, and thus, identification of molecules that can counteract the neurotoxicity of ethanol deserves high priority. Since activation of potassium (K+) currents has been shown to play a critical role in the control of programmed cell death, we have investigated the effects of ethanol and PACAP on K+ currents in cultured cerebellar granule cells using the patch-clamp technique in the whole cell configuration. In the presence of the fast-inactivating IA current blocker 4-AP, a focal application of ethanol (200 mM) in the vicinity of granule cells provoked a robust hyperpolarization and a marked increase of the delayed rectifier IK current. Addition of PACAP (0.1 microM) in the bath solution prevented ethanol-induced membrane hyperpolarization and suppressed the stimulatory effect of ethanol on IK current. These data suggest that ethanol alters neuronal survival, at least in part, through activation of IK, and that PACAP abolishes ethanol-induced cerebellar granule cell death via inhibition of IK..

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“…PACAP and its receptors are actively expressed in the rat cerebellar cortex during postnatal development (Basille et al ., 1993; Nielsen et al ., 1998; Gonzalez et al ., 2002). In particular, high levels of PAC1‐R are found in the external granule cell layer, a germinative matrix that gives rise to cerebellar interneurons (Basille et al ., 2000).…”

Section: Introductionmentioning

confidence: 99%

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

Mei

Vaudry

Basille

et al. 2004

Eur J of Neuroscience

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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.

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Function of PACAP in the Central Nervous System

Cited by 3 publications

References 168 publications

VIP–PACAP System in Immunity

VIP–PACAP System in Immunity

The Delayed Rectifier Channel Current I_K Plays a Key Role in the Control of Programmed Cell Death by PACAP and Ethanol in Cerebellar Granule Neurons

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

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Function of PACAP in the Central Nervous System

Cited by 3 publications

References 168 publications

VIP–PACAP System in Immunity

VIP–PACAP System in Immunity

The Delayed Rectifier Channel Current IK Plays a Key Role in the Control of Programmed Cell Death by PACAP and Ethanol in Cerebellar Granule Neurons

PACAP inhibits delayed rectifier potassium current via a cAMP/PKA transduction pathway: evidence for the involvement of IK in the anti‐apoptotic action of PACAP

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The Delayed Rectifier Channel Current I_K Plays a Key Role in the Control of Programmed Cell Death by PACAP and Ethanol in Cerebellar Granule Neurons

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