Excitatory action of pituitary adenylate cyclase activating polypeptide on rat sympathetic preganglionic neurons in vivo and in vitro

Lai, Chih-Chia; Wu, Su-Ying; Lin, Hsun-Hsun; Dun, Nae J.

doi:10.1016/s0006-8993(96)01297-8

Cited by 46 publications

(45 citation statements)

References 17 publications

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“…Our data show that intrathecal injection of PACAP-38 at T5-6 increases splanchnic sympathetic nerve activity and heart rate but has no significant effect on arterial pressure. The effects on sympathetic outflow support findings that PACAP-38 excites sympathetic preganglionic neurons in spinal cord slices from juvenile rats (11). However, our finding that blood pressure is unaffected contrasts with one previous study that found a pressor response evoked by intrathecal administration of PACAP-38.…”

Section: Discussionsupporting

confidence: 84%

PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo

Farnham¹,

Li²,

Goodchild³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Farnham MMJ, Li Q, Goodchild AK, Pilowsky PM. PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo. Am J Physiol Regul Integr Comp Physiol 294: R1304-R1311, 2008. First published February 13, 2008 doi:10.1152/ajpregu.00753.2007.-Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide present in the rat brain stem. The extent of its localization within catecholaminergic groups and bulbospinal sympathoexcitatory neurons is not established. Using immunohistochemistry and in situ hybridization, we determined the extent of any colocalization with catecholaminergic and/or bulbospinal projections from the brain stem was determined. PACAP mRNA was found in tyrosine hydroxylaseimmunoreactive (TH-ir) neurons in the C1-C3 cell groups. In the rostral ventrolateral medulla (RVLM), PACAP mRNA was found in 84% of the TH-ir neurons and 82% of bulbospinal TH-ir neurons. The functional significance of these PACAP mRNA positive bulbospinal neurons was tested by intrathecal administration of PACAP-38 in anaesthetized rats. Splanchnic sympathetic nerve activity doubled (110%) and heart rate rose significantly (19%), although blood pressure was unaffected. In addition, as previously reported, PACAP was found in the A1 cell group but not in the A5 cell group or in the locus coeruleus. The RVLM is the primary site responsible for the tonic and reflex control of blood pressure through the activity of bulbospinal presympathetic neurons, the majority of which contain TH. The results indicate 1) that pontomedullary neurons containing both TH and PACAP that project to the intermediolateral cell column originate from C1-C3 and not A5, and 2) intrathecal PACAP-38 causes a prolonged, sympathoexcitatory effect.

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Section: Discussionsupporting

confidence: 84%

PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo

Farnham¹,

Li²,

Goodchild³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Functional evidence supports these findings; intrathecal PACAP-38 causes a prolonged tachycardia and sympathoexcitation in multiple sympathetic beds through activation of SPN, but no change in MAP (9,19). Previous studies report conflicting findings regarding the MAP response to PACAP-38; Lai et al (25) found a significant increase in MAP (25), while others saw no change in MAP (9). This study supports the earlier findings that PACAP-38 does not affect MAP in vivo (9,19).…”

Section: Pacap-38 Alone Alters Tonic But Not Reflex Control Of the supporting

confidence: 87%

“…The excitatory effects of PACAP-38 are well characterized in the cardiovascular system (10,54). PACAP-38 excites SPN in spinal cord slices from juvenile rats (25) and is localized in at least 82% of C1 presympathetic bulbospinal RVLM neurons (9). Functional evidence supports these findings; intrathecal PACAP-38 causes a prolonged tachycardia and sympathoexcitation in multiple sympathetic beds through activation of SPN, but no change in MAP (9,19).…”

Section: Pacap-38 Alone Alters Tonic But Not Reflex Control Of the mentioning

confidence: 81%

Catestatin has an unexpected effect on the intrathecal actions of PACAP dramatically reducing blood pressure

Gaede

Inglott

Farnham

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Gaede AH, Inglott MA, Farnham MM, Pilowsky PM. Catestatin has an unexpected effect on the intrathecal actions of PACAP dramatically reducing blood pressure. Am J Physiol Regul Integr Comp Physiol 303: R719 -R726, 2012. First published August 8, 2012 doi:10.1152/ajpregu.00202.2012.-This study focuses on presympathetic neurons of the rostral ventrolateral medulla (RVLM) that regulate sympathetic vasomotor tone. Many neurotransmitters are colocalized in RVLM neurons and are released under specific conditions to modulate efferent homeostatic responses. Of particular interest here are two peptides colocalized in catecholaminergic RVLM neurons: catestatin and pituitary adenylate cyclase-activating polypeptide (PACAP). Chromogranin A-derived catestatin is a potent endogenous noncompetitive nicotinic and adrenoreceptor antagonist. Catestatin impairs adenylate cyclase and phospholipase C action: mechanisms engaged by PACAP. Although PACAP and catestatin are likely coreleased, the possible effects of this are unknown. We aimed to determine whether catestatin affects the normal sympathoexcitatory but isotensive responses to intrathecal PACAP. Urethane-anesthetized, vagotomized, ventilated Sprague-Dawley rats (n ϭ 22) were given an intrathecal injection of catestatin at different times prior to intrathecal administration of PACAP-38. Arterial pressure, splanchnic sympathetic nerve activity, heart rate, and reflex responses to baroreceptor and chemoreceptor activation were recorded. The key findings of this study are that pretreatment with catestatin time dependently enhances the PACAP-38 effect on mean arterial pressure and enhances sympathetic barosensitivity and chemosensitivity. The timescale of the effect of catestatin on the response to PACAP-38 strongly suggests that catestatin is either causing changes in gene expression to exert its effects, or modifying intracellular mechanisms normally engaged by PAC 1 receptors. The ability of catestatin pretreatment to enhance barosensitivity and chemosensitivity after PACAP-38 injection supports the hypothesis that catestatin manipulates the intracellular environment within sympathetic neurons in a way that increases responses to PACAP. chromogranin a; sympathetic; baroreflex; chemoreflex; epinephrine HYPERTENSION IS A MAJOR HUMAN health problem that is due, in large part, to increased sympathetic drive that emanates from the rostral ventrolateral medulla (RVLM) (42,44,45). Central neural mechanisms maintain arterial blood pressure by integrating information from reflexes and central behavioral and emotional states to alter efferent sympathetic and parasympathetic activity, according to need (18,44,45). The RVLM plays a critical role in this system as the final integrative pathway in the regulation of sympathetic tone and cardiovascular adaptive reflexes (e.g., the baroreceptor and chemoreceptor reflexes) (45). The RVLM contains a functionally heterogeneous cell population that includes barosensitive, presympathetic (C1) neurons, which project to sympathetic preganglionic neu...

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“…PACAP(1-38) was found to enhance NMDA receptor function in chick cortical neurons (24), in sympathetic preganglionic neurons (25), and in the CA1 region of the hippocampus (26). However, the molecular mechanism that mediates PACAP induction of NMDA receptor activity is unknown.…”

Section: Forskolin and Pacap(1-38) Enhance Nmda Receptor-mediated Fepmentioning

confidence: 99%

Pituitary Adenylate Cyclase-activating Polypeptide (PACAP(1–38)) Enhances N-Methyl-d-aspartate Receptor Function and Brain-derived Neurotrophic Factor Expression via RACK1

Yaka

Phamluong

et al. 2003

Journal of Biological Chemistry

160

189

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A. 99, 5710 -5715). Here, we identified the signaling cascade by which RACK1 is released from the NMDA receptor complex and identified the consequences of the dissociation. We found that activation of the cAMP/protein kinase A pathway in hippocampal slices induced the release of RACK1 from NR2B and Fyn. This resulted in the induction of NR2B phosphorylation and the enhancement of NMDA receptor-mediated activity via Fyn. We identified the neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP(1-38)), as a ligand that induced phosphorylation of NR2B and enhanced NMDA receptor potentials. Finally, we found that activation of the cAMP/protein kinase A pathway induced the movement of RACK1 to the nuclear compartment in dissociated hippocampal neurons. Nuclear RACK1 in turn was found to regulate the expression of brain-derived neurotrophic factor induced by PACAP(1-38). Taken together our results suggest that activation of adenylate cyclase by PACAP(1-38) results in the release of RACK1 from the NMDA receptor and Fyn. This in turn leads to NMDA receptor phosphorylation, enhanced activity mediated by Fyn, and to the induction of brain-derived neurotrophic factor expression by RACK1. The ionotropic glutamate receptor subtype, N-methyl-D-as-1 plays an essential role in neuronal development, excitotoxicity, synaptic plasticity, and learning and memory (2). The ligand-gated NMDA receptor channel is a heteromer comprised of NR1 and at least one of four NR2 subunits (A-D) (3). The cytoplasmic tail of the NR2B subunit is phosphorylated on tyrosine residues (4) and is the most abundant tyrosine-phosphorylated protein in the postsynaptic density (5). Phosphorylation of NMDA receptor subunits regulates the activity of the channel (6). Specifically, application of a tyrosine kinase inhibitor causes a progressive decrease in NMDA receptor-mediated currents, and conversely, inhibition of protein-tyrosine phosphatases results in an increase in NMDA receptor-mediated currents (7). Subsequent studies have identified the Src family of protein-tyrosine kinases (PTKs) as enzymes that phosphorylate the NR2 subunits, regulating NMDA receptor activities (6 -8). Hence, modulation of NMDA receptor phosphorylation by Src family protein-tyrosine kinases is likely to play an important role in modulating glutamate-mediated pathways. In the recent years it has become increasingly apparent that the formation of localized signaling complexes, which include receptors, kinases, phosphatases and their substrates, are highly important for the regulation of signal transduction cascades (9, 10). Scaffolding proteins play a major role in the assembly of such signaling complexes (11). Recently, we identified the scaffolding protein RACK1 as a novel regulator of the phosphorylation state and function of the NMDA receptor. We found that RACK1 interacts with both the cytoplasmic tail of the NR2B subunit and Fyn and inhibits the ability of Fyn to phosphorylate the NR2B subunit and consequently inhibits NMDA receptor-mediated excitatory postsyna...

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Excitatory action of pituitary adenylate cyclase activating polypeptide on rat sympathetic preganglionic neurons in vivo and in vitro

Cited by 46 publications

References 17 publications

PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo

PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo

Catestatin has an unexpected effect on the intrathecal actions of PACAP dramatically reducing blood pressure

Pituitary Adenylate Cyclase-activating Polypeptide (PACAP(1–38)) Enhances N-Methyl-d-aspartate Receptor Function and Brain-derived Neurotrophic Factor Expression via RACK1

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