Regular ArticlePituitary Adenylate Cyclase Activating Polypeptide (PACAP) and Its Receptors: Neuroendocrine and Endocrine Interaction
Abstract
The recent progress of research on the functions of pituitary adenylate cyclase activating polypeptide (PACAP), especially endocrine and neuroendocrine interactions, is described. Studies of the genes encoding the PACAP precursor and the type I PACAP receptor provide information on the control of PACAP gene expression and on the relationship between the structure of the receptor subtypes and the activation of various signal transduction pathways. The availability of specific antisera against PACAP and the type I PACAP receptor made it possible to examine their distributions in the brain and other tissues. Immunohistochemical studies and physiological studies with synthetic PACAP indicate that PACAP is a new type of hypophysiotropic hormone and also functions as a neurotransmitter, neuromodulator, and neurotrophic factor in the central nervous system. The abundance of PACAP and its type I receptors in the adrenal medulla and the results of studies with synthetic PACAP suggest that PACAP is a potent noncholinergic secretogue for catecholamines. PACAP and its receptors are also present in the pancreas and appear to play a regulatory role in insulin secretion at extremely low concentrations in a glucose-dependent manner. Immunohistochemical demonstration of PACAP and its receptors in the testicular spermatids at early stages suggests an important role of testicular PACAP in spermiogenesis. Together with its actions on pituitary gonadotropes, this suggests that it plays a key role in reproduction.
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Neuroprotective effect of the PACAP-ADNP axis on SOD1G93A mutant motor neuron death induced by trophic factors deprivation
2023, NeuropeptidesAmyotrophic lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons in the central nervous system. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) account for approximately in 20% of familial ALS cases. The pathological mechanisms underlying the toxicity induced by mutated SOD1 are still unknown. However, it has been hypothesized that oxidative stress (OS) has a crucial role in motor neuron degeneration in ALS patients. Moreover, it has been described that SOD1 mutation interferes expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a protective key modulator against OS and reactive oxygen species (ROS) formation.
The protective effect of pituitary adenylate cyclase-activating peptide (PACAP) has been demonstrated in various neurological disorders, including ALS. Some of its effects are mediated by the stimulation of an intracellular factor known as activity-dependent protein (ADNP). The role of PACAP-ADNP axis on mutated SOD1 motor neuron degeneration has not been explored, yet. The present study aimed to investigate whether PACAP prevented apoptotic cell death induced by growth factor deprivation through ADNP activation and whether the peptidergic axis can counteract the OS insult.
By using an in vitro model of ALS, we demonstrated that PACAP by binding to PAC1 receptor (PAC1R) prevented motor neuron death induced by serum deprivation through induction of the ADNP expression via PKC stimulation. Furthermore, we have also demonstrated that the PACAP/ADNP axis counteracted ROS formation by inducing translocation of the Nfr2 from the cytoplasm to the nucleus. In conclusion, our study provides new insights regarding the protective role of PACAP-ADNP in ALS.
Protective effect of pituitary adenylate cyclase activating polypeptide in diabetic keratopathy
2023, PeptidesDiabetic keratopathy (DK) is the major complication of the cornea characterizing diabetes-affected patients. This ocular pathology is correlated with the hyperglycemic state leading to delayed corneal wound healing and recurrent corneal ulcers. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with widespread distribution throughout the body, and exerting cytoprotective effects in the neural and non-neuronal parts of the eye, including the cornea. The purpose of the present study was to investigate whether changes in PACAP expression can concur for delayed epithelial wound healing in diabetic cornea and whether the protective effect of the peptide could be mediated through the activation of the EGFR signaling pathway, which has been reported to be impaired in DK. Expression and distribution of PACAP, PAC1R, and EGFR were investigated through immunohistochemistry analysis in the cornea of normal and diabetic rats. The role of the peptide on wound healing during DK was evaluated in an in vitro model represented by rabbit corneal epithelial cells grown in high glucose conditions. Western blotting and immunofluorescence analysis were used to examine the ability of PACAP to induce the activation of the EGFR/ERK1/2 signaling pathway. Our results showed that in diabetic cornea the expression of PACAP, PAC1R, and EGFR is drastically reduced. The treatment with PACAP via PAC1R activation enhanced cell viability and corneal epithelium wound healing in cells grown under high glucose conditions. Furthermore, both EGFR and ERK1/2 signaling was induced upon the peptide treatment. Overall, our results showed the trophic efficiency of PACAP for enhancing the corneal epithelium re-epithelialization suggesting that the peptide could be beneficially valuable as a treatment for DK.
Role of PACAP in migraine: An alternative to CGRP?
2023, Neurobiology of DiseaseCitation Excerpt :PACAP is found in two functional isoforms: PACAP38 which consists of 38 amino acids and the truncated 27 amino acid form (PACAP27) (Miyata et al., 1990). PACAP38 is the primary isoform representing approximately 90% of total PACAP in the body (Arimura and Shioda, 1995) whereas PACAP27 represents 10% and is less studied (Vaudry et al., 2009). Both isoforms act on the same receptors with similar affinity and function (Vaudry et al., 2000).
Migraine is a widespread and debilitating neurological condition affecting more than a billion people worldwide. Thus, more effective migraine therapies are highly needed. In the last decade, two endogenous neuropeptides, calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP), were identified to be implicated in migraine. Recently, introduction of monoclonal antibodies (mAbs) blocking the CGRP is the most important advance in migraine therapy for decades. However, 40% of patients are unresponsive to these new drugs. We believe that PACAP may be involved in these patients. Like CGRP, PACAP is located to sensory nerve fibers, it dilates cranial arteries, it causes migraine when infused into patients and it is a peptide that lends itself to antibody therapy. Also, recent studies suggest that the PACAP pathway is independent of the CGRP pathway. Understanding the signaling pathways of PACAP may therefore lead to identification of novel therapeutic targets of particular interest in patients unresponsive to anti-CGRP therapy. Accordingly, neutralizing mAb to PACAP is currently in clinical phase II development. The aim of the present review is, therefore, to give a thorough account of the existing data on PACAP, its receptors and its relation to migraine.
VIPergic neuroprotection in epileptogenesis: challenges and opportunities
2021, Pharmacological ResearchIn mesial temporal lobe epilepsy (MTLE), seizures typically arise in the hippocampus or other mesial temporal lobe structures. The aetiology of MTLE epileptogenesis in still unknown, yet putative precipitating events such as trauma, complex febrile seizures, status epilepticus, inflammatory insults, or ischemia have been implicated. MTLE is commonly associated to a high degree of hippocampal sclerosis (HS) leading to frequent anti-epileptic drug refractoriness. Thus, the aim of recent therapeutic strategies has shifted from control of symptomatic seizures to putative prevention of epileptogenic processes. Vasoactive intestinal peptide (VIP) acts as a neurotransmitter, neurotrophic or neuroprotective factor in the central nervous system (CNS), also displaying anti-inflammatory and neurogenic actions. In the hippocampus, a brain area implicated in learning and memory, VIP released from basket cells and/or interneuron-selective interneurons controls GABAergic transmission and pyramidal cell activity influencing hippocampal-dependent synaptic plasticity (long-term potentiation and long-term depression) and cognition. VPAC1 receptor activation enhances hippocampal synaptic transmission by fostering disinhibition, while stimulation of VPAC2 receptors favours pyramidal cell excitability. Interestingly, VIP released from interneurons has potent anti-inflammatory actions, participates in the maintenance of the blood-brain barrier integrity, and strengthens neurogenesis. VPAC1 and VPAC2 receptors play differential roles in the regulation of the neuro-immune interactions. In this context, we gathered here the available information concerning the impact of VIP on neurotransmission and neuronal excitability in MTLE-HS and discuss the preventive use of selective VIP receptor ligands to abrogate epileptogenesis in MTLE-HS by controlling synaptic plasticity, neurogenesis and neuronal survival, neuroinflammation, and blood-brain barrier damage.
PAC1 deficiency attenuates progression of atherosclerosis in ApoE deficient mice under cholesterol-enriched diet
2020, ImmunobiologyThe neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP) is vasoactive and cytoprotective and exerts immunoregulatory functions throughout the nervous, neuroendocrine cardiovascular and immune systems in health and disease. PACAP mainly acts through PAC1 receptor signaling in neuronal communication, but the role of PAC1 in immune regulation of atherosclerosis is not known. Here, we generated PAC1−/−/ApoE−/− mice to test, whether PAC1−/− influences plasma cholesterol-/triglyceride levels and/or atherogenesis in the brachiocephalic trunk (BT) seen in ApoE−/− mice, under standard chow (SC) or cholesterol-enriched diet (CED). Furthermore, the effect of PAC1−/−, on inflammatory, autophagy-, apoptosis- and necroptosis-relevant proteins in atherosclerotic plaques was determined. In plaques of PAC1−/−/ApoE−/− mice fed a SC, the immunoreactivity for apoptotic, autophagic, necroptotic and proinflammatory proteins was increased, however, proliferation was unaffected. Interestingly, without affecting hyperlipidemia, PAC1−/− in ApoE−/− mice remarkably reduced CED-induced lumen stenosis seen in ApoE−/− mice. Thus, PAC1−/− allows unchecked inflammation, necroptosis and decreased proliferation during SC, apparently priming the BT to develop reduced atheroma under subsequent CED. Remarkably, no differences in inflammation/necroptosis signatures in the atheroma under CED between PAC1−/−/ApoE−/− and ApoE−/− mice were observed. These data indicate that selective PAC1 antagonists should offer potential as a novel class of atheroprotective therapeutics, especially during hypercholesterolemia.
Protective effect of PACAP against ultraviolet B radiation-induced human corneal endothelial cell injury
2020, NeuropeptidesThe human cornea, a sophisticated example of natural engineering, is composed in the innermost layer by endothelial cells maintaining stromal hydration and clarity. Different types of insults, including ultraviolet (UV) radiations, can lead to corneal opacity due to their degenerative and limited proliferative capability.
In our previous studies, we have shown the protective effects of pituitary adenylate cyclase activating polypeptide (PACAP) in human corneal endothelial cells (HCECs), after growth factors deprivation.
The aim of the present work has been to investigate the effect of this peptide on UV-B-induced HCECs injury. The results have shown that UV-B irradiations induced apoptotic cells death and consequently alteration in human corneal endothelial barrier.
We found that PACAP treatment significantly increased viability, trans-endothelial electrical resistance and tight junctions expression of HCECs exposed to UV-B insult.
In conclusion, data have suggested that this peptide could have protective effect to preserve the physiological state of human corneal endothelium exposed to UV-B damage.