Molecular and Conformational Determinants of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) for Activation of the PAC1 Receptor

2009 ◽  
Vol 52 (10) ◽  
pp. 3308-3316 ◽  
Author(s):  
Steve Bourgault ◽  
David Vaudry ◽  
Isabelle Ségalas-Milazzo ◽  
Laure Guilhaudis ◽  
Alain Couvineau ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Pac1 Receptor ◽  
Pituitary Adenylate Cyclase

Pituitary adenylate cyclase activating polypeptide and PAC1 receptor signaling increase Homer 1a expression in central and peripheral neurons

2004 ◽  
Vol 123 (1-3) ◽  
pp. 107-116 ◽  
Author(s):  
Beatrice M. Girard ◽  
Emily T. Keller ◽  
Kristin C. Schutz ◽  
Victor May ◽  
Karen M. Braas
Keyword(s):  
Adenylate Cyclase ◽  
Receptor Signaling ◽  
Pac1 Receptor ◽  
Peripheral Neurons ◽  
Pituitary Adenylate Cyclase

scholarly journals Presence of Systemic Amyloidosis in Mice with Partial Deficiency in Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Aging

2021 ◽  
Vol 11 (16) ◽  
pp. 7373
Author(s):  
Jason Sparks ◽  
Adel Jungling ◽  
Gabriella Kiss ◽  
Laszlo Hiripi ◽  
Daniel Pham ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Accelerated Aging ◽  
Blood Analysis ◽  
Histopathological Analysis ◽  
Limited Data ◽  
Pac1 Receptor ◽  
Amyloid Deposits ◽  
Pituitary Adenylate Cyclase ◽  
Quantitative Changes ◽  
Partial Deficiency

Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide with widespread expression and general cytoprotective effects, is also involved in aging. Previously, we observed accelerated systemic senile amyloidosis in PACAP knockout (KO) mice. As mice partially lacking PACAP (heterozygous-HZ) show variable symptoms, here we investigated whether HZ mice have accelerated aging, completed with observations in PAC1 receptor KO mice. As we have limited data on qualitative or quantitative changes in the blood of PACAP-deficient mice, we investigated whether these changes could be in the background of the amyloidosis. Routine histological staining was used to examine amyloid deposits, rated on a severity scale 0–3. Blood was collected from PACAP wild type/HZ mice for complete blood analysis. In contrast to receptor KO mice showing no amyloidosis, histopathological analysis revealed severe deposits in PACAP HZ mice, with kidney, spleen, skin, and intestines being most affected. Increased cholesterol, lipoprotein levels, and differences in several blood count parameters were found in HZ mice. In summary, amyloidosis also develops in partial absence of PACAP, in contrast to the lack of its PAC1 receptor. In addition to the earlier identified inflammatory and degenerative disturbances, the alteration in lipid metabolism and bone marrow activity can also be additional factors leading to systemic degenerative processes.

scholarly journals A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a pituitary adenylate cyclase-activating polypeptide PAC1 receptor monoclonal antibody for migraine prevention

Cephalalgia ◽  
2020 ◽  
pp. 033310242097088
Author(s):  
Messoud Ashina ◽  
David Doležil ◽  
Jo H Bonner ◽  
Lifen Zhou ◽  
Jan Klatt ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Controlled Trial ◽  
Episodic Migraine ◽  
Migraine Prevention ◽  
Phase 2 ◽  
Pac1 Receptor ◽  
Double Blind ◽  
Treatment Groups ◽  
Pituitary Adenylate Cyclase

Objective To assess the safety and efficacy of AMG 301, an inhibitor of the pituitary adenylate cyclase-activating polypeptide (PACAP)-1 (PAC1) receptor, for prevention of migraine. Methods In a double-blind trial, patients were randomized 4:3:3 to placebo, AMG 301 210 mg every 4 weeks, or AMG 301 420 mg every 2 weeks for 12 weeks. Effect on monthly migraine days and other secondary measures were assessed over weeks 9–12. Safety and tolerability were assessed. Results Of 343 randomized patients (mean age, 41.8–42.5 years), the majority were women (85.4–90.4%), white (94.1–96.2%), and had episodic migraine (62.5–67.9%). A total of 305 patients completed treatment (placebo, n = 124; AMG 301 210 mg, n = 94; AMG 301 420 mg, n = 87). Least squares mean reduction at week 12 in monthly migraine days from baseline was −2.5 (0.4) days for placebo and −2.2 (0.5) days for both AMG 301 treatment groups. No difference between AMG 301 and placebo on any measure of efficacy was observed; mean (95% confidence interval) treatment difference versus placebo for monthly migraine days for AMG 301 210 mg, 0.3 (−0.9 to 1.4); AMG 301 420 mg, 0.3 (−0.9 to 1.4). The incidence of adverse events was similar across groups. Conclusion AMG 301 offered no benefit over placebo for migraine prevention; further studies may be necessary to fully understand the role of PACAP isoforms and its receptors in migraine pathophysiology. Study Registration ClinicalTrials.gov: NCT03238781

Pituitary adenylate cyclase-activating polypeptide type 1 (PAC1) receptor is expressed during embryonic development of the earthworm

2010 ◽  
Vol 339 (3) ◽  
pp. 649-653 ◽  
Author(s):  
Ákos Boros ◽  
Ildikó Somogyi ◽  
Péter Engelmann ◽  
Andrea Lubics ◽  
Dóra Reglodi ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Adenylate Cyclase ◽  
Pac1 Receptor ◽  
Pituitary Adenylate Cyclase

scholarly journals Pituitary adenylate cyclase activating polypeptide concentrations in the sheep mammary gland, milk, and in the lamb blood plasma after suckling

2020 ◽  
Vol 107 (1) ◽  
pp. 92-105
Author(s):  
K. Pohóczky ◽  
A. Tamás ◽  
D. Reglődi ◽  
Á. Kemény ◽  
Zs. Helyes ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Adenylate Cyclase ◽  
Pac1 Receptor ◽  
Bdnf Mrna ◽  
Daily Cycle ◽  
Milk Whey ◽  
Rapid Absorption ◽  
Pituitary Adenylate Cyclase ◽  
Age Dependent ◽  
Level 2

AbstractPituitary adenylate cyclase activating polypeptide (PACAP) is involved in development and reproduction. We previously described elevated PACAP levels in the milk compared to the plasma, and the presence of its specific PAC1 receptor in the mammary gland. This study aimed to determine PACAP and vasoactive intestinal peptide (VIP) levels in female suckling lambs compared to ewe plasma and mammary gland, as well as their age-dependent alterations. mRNA expressions of PACAP, VIP, PAC1 receptor and brain-derived neurotrophic factor (BDNF) were quantified in the milk whey and mammary gland. PACAP38-like immunoreactivity (PACAP38-LI) was measured in plasma, milk whey and mammary gland by radioimmunoassay, VIP-LI by enzyme-linked immunoassay. PACAP38-LI was 5, 6 times higher in the milk compared to the plasma of lactating sheep. It significantly increased in the lamb plasma 1 h, but returned to basal level 2 h after suckling. However, VIP mRNA was not present in the mammary gland, we detected the VIP protein in the milk whey. BDNF mRNA significantly decreased with age to approximately 60% and 25% in the 3- and 10-year-old sheep respectively, compared to the 3-month-old lambs. No differences were found between mammary and jugular vein plasma PACAP and VIP concentrations, or during the daily cycle. We propose a rapid absorption of PACAP38 from the milk and/or its release in suckling lambs. PACAP accumulated in the milk might be synthesized in the mammary gland or secreted from the plasma of the mothers. PACAP is suggested to have differentiation/proliferation promoting and immunomodulatory effects in the newborns and/or a local function in the mammary gland.

scholarly journals Spinal astrocyte-neuron lactate shuttle contributes to the pituitary adenylate cyclase-activating polypeptide/PAC1 receptor-induced nociceptive behaviors in mice

2021 ◽  
Author(s):  
Yuki Kambe ◽  
Masafumi Yokai ◽  
Ichiro Takasaki ◽  
Takashi Kurihara ◽  
Atsuro Miyata
Keyword(s):  
Adenylate Cyclase ◽  
Intrathecal Administration ◽  
Spinal Nerve ◽  
Pac1 Receptor ◽  
Lactate Shuttle ◽  
Kinase C ◽  
Pituitary Adenylate Cyclase ◽  
Astroglial Activation

Abstract We have previously showed that spinal pituitary adenylate cyclase-activating polypeptide (PACAP)/PACAP type 1 (PAC1) receptor signaling triggered long-lasting nociceptive behaviors through astroglial activation in mice. Since astrocyte-neuron lactate shuttle (ANLS) could be essential for long-term synaptic facilitation, we aimed to elucidate a possible involvement of spinal ANLS in the development of the PACAP/PAC1 receptor-induced nociceptive behaviors. A single intrathecal administration of PACAP induced short-term spontaneous aversive behaviors, followed by long-lasting mechanical allodynia in mice. These nociceptive behaviors were inhibited by 1,4-dideoxy-1,4-imino-d-arabinitol (DAB), an inhibitor of glycogenolysis, and this inhibition was reversed by simultaneous L-lactate application. In the cultured spinal astrocytes, the PACAP-evoked glycogenolysis and lactate secretion were inhibited by DAB. In addition, a protein kinase C (PKC) inhibitor attenuated the PACAP-induced nociceptive behaviors as well as the PACAP-evoked glycogenolysis and lactate secretion. Finally, an inhibitor for the monocarboxylate transporters blocked the lactate secretion from the spinal astrocytes and inhibited the PACAP- and spinal nerve ligation-induced nociceptive behaviors. These results suggested that spinal PAC1 receptor-PKC-ANLS signaling contributed to the PACAP-induced nociceptive behaviors. This signaling system could be involved in the peripheral nerve injury-induced pain-like behaviors.

scholarly journals Pituitary Adenylate Cyclase-Activating Polypeptide in Learning and Memory

2021 ◽  
Vol 15 ◽  
Author(s):  
Marieke R. Gilmartin ◽  
Nicole C. Ferrara
Keyword(s):  
Adenylate Cyclase ◽  
Fear Learning ◽  
Traumatic Experience ◽  
Affective Processing ◽  
Receptor Signaling ◽  
Post Traumatic Stress ◽  
Pac1 Receptor ◽  
Pituitary Adenylate Cyclase ◽  
Learning And Plasticity ◽  
Neuronal Physiology

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved neuropeptide that regulates neuronal physiology and transcription through Gs/Gq-coupled receptors. Its actions within hypothalamic, limbic, and mnemonic systems underlie its roles in stress regulation, affective processing, neuroprotection, and cognition. Recently, elevated PACAP levels and genetic disruption of PAC1 receptor signaling in humans has been linked to maladaptive threat learning and pathological stress and fear in post-traumatic stress disorder (PTSD). PACAP is positioned to integrate stress and memory in PTSD for which memory of the traumatic experience is central to the disorder. However, PACAP’s role in memory has received comparatively less attention than its role in stress. In this review, we consider the evidence for PACAP-PAC1 receptor signaling in learning and plasticity, discuss emerging data on sex differences in PACAP signaling, and raise key questions for further study toward elucidating the contribution of PACAP to adaptive and maladaptive fear learning.

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