Pituitary adenylate cyclase activating polypeptide expression in sensory neurons

doi:10.1016/0306-4522(94)90025-6

Neuroscience

Volume 63, Issue 1, November 1994, Pages 307-312

https://doi.org/10.1016/0306-4522(94)90025-6 Get rights and content

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel vasoactive intestinal peptide (VIP)-like peptide isolated from ovine hypothalami. The presence of PACAP-like immunoreactivity was recently demonstrated in nerve cell bodies of sensory ganglia in the rat. Since PACAP belongs to a large family of chemically related neuropeptides, we have, in the present study, tried to establish the synthesis of PACAP in neurons of sensory ganglia, usingin situ hybridization with a³⁵S-labelled oligonucleotide probe complementary to PACAP mRNA. The expression of PACAP was compared to that of calcitonin gene-related peptide (CGRP) using a radiolabelled CGRP oligonucleotide probe. The PACAP probe labelled small to medium-sized neurons in the trigeminal ganglion and dorsal root ganglia at different levels, indicating the presence of PACAP mRNA. The CGRP probe labelled nerve cell bodies of varying size, outnumbering those labelled by the PACAP probe. In dorsal root ganglia, cells expressing PACAP constitutedc. 10% and those expressing CGRP 46% of the total number of nerve cell bodies. Expression of PACAP was seen in a small subpopulation of cells expressing CGRP.

We conclude that PACAP is synthesized in a subpopulation of neurons of sensory anglia in the rat. Therefore, the recently described effects of PACAP—cutaneous vasodilation, potentiation of oedema formation and depression of nociceptive spinal reflexes—may be physiological and related to neurogenic inflammation and modulation of pain transmission.

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The cornea is richly innervated with sensory nerves that function to detect and clear harmful debris from the surface of the eye, promote growth and survival of the corneal epithelium and hasten wound healing following ocular disease or trauma. Given their importance to eye health, the neuroanatomy of the cornea has for many years been a source of intense investigation. Resultantly, complete nerve architecture maps exist for adult human and many animal models and these maps reveal few major differences across species. Interestingly, recent work has revealed considerable variation across species in how sensory nerves are acquired during developmental innervation of the cornea. Highlighting such species-distinct key differences, but also similarities, this review provides a full, comparative anatomy analysis of sensory innervation of the cornea for all species studied to date. Further, this article comprehensively describes the molecules that have been shown to guide and direct nerves toward, into and through developing corneal tissue as the final architectural pattern of the cornea’s neuroanatomy is established. Such knowledge is useful for researchers and clinicians seeking to better understand the anatomical and molecular basis of corneal nerve pathologies and to hasten neuro-regeneration following infection, trauma or surgery that damage the ocular surface and its corneal nerves.
Role of PACAP in migraine: An alternative to CGRP?
2023, Neurobiology of Disease
Citation Excerpt :
These effects might be responsible for the long-lasting flushing and delayed migraine attacks observed after PACAP38 infusion in man. PACAP38 is present in the sensory nervous system and has been identified in first-order neurons in the trigeminal ganglion (Eftekhari et al., 2015a; Mulder et al., 1994) and in second-order neurons in the TNC (Tuka et al., 2012; Uddman et al., 2002). The three classical PACAP38 receptors have been detected in both the trigeminal ganglion (Knutsson and Edvinsson, 2002) and TNC (Shioda et al., 1997).
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.
The novel small-molecule antagonist of PAC1 receptor attenuates formalin-induced inflammatory pain behaviors in mice
2019, Journal of Pharmacological Sciences
We recently developed PA-8, a novel small-molecule antagonist of PACAP type 1 (PAC1) receptor. In the present study, we examined whether PA-8 was effective against formalin-induced inflammatory pain in mice. Both intrathecal and oral administration of PA-8 resulted in the dose-dependent attenuation of the second phase of formalin-induced nociceptive responses. PA-8 also inhibited c-fos upregulation in the ipsilateral dorsal horn of the spinal cord. The results suggested that PACAP-PAC1 receptor signaling system in the spinal cord were primarily involved in the transmission of inflammatory pain, and PA-8 could be useful for the development of novel analgesics for treating inflammatory pain.
Trophic effect of PACAP on human corneal endothelium
2018, Peptides
Citation Excerpt :
Furthermore, it exerts a beneficial role in different neurodegenerative diseases and wide variety of tumors [21–27]. PACAP and its receptors are also localized in various regions of the eye, such as retina, uvea, trigeminal ganglion cells, iris sphincter, ciliary body and cornea [28–31]. Different studies have demonstrated that this peptide stimulates tear production, protects retina against diabetic damage and promotes epithelial corneal wound repair [32–36].
Cornea’s posterior surface includes endothelium maintaining stromal hydration and clarity. Due to their limited proliferative capability, the loss of endothelial cells can outcome in permanent opacity.
In the last years, different studies have demonstrated the protective effect of pituitary adenylate cyclase-activating polypeptide (PACAP) in different ocular diseases. However, its role on human corneal endothelial cells (HCECs) has not been investigated, yet.
Here, we have developed a culture protocol to differentiate HCECs from donor’s cornea. PACAP treatment prevented damage induced by growth factors deprivation of cells grown on transwell supports as revealed by TERR measurements. Moreover, this peptide significantly increased tight junction proteins expression by conferring resistance to endothelial barrier. This effect is also related to promotion of cell viability as demonstrated by MTT assay. Furthermore, PACAP stimulated repairing of corneal endothelium lesion as shown by wound healing analysis.
In conclusion, our data suggest that this peptide could represent an important trophic factor in maintaining functionality of human corneal endothelium.
Pituitary adenylate cyclase-activating polypeptide type 1 receptor signaling evokes long-lasting nociceptive behaviors through the activation of spinal astrocytes in mice
2016, Journal of Pharmacological Sciences
Intrathecal (i.t.) administration of pituitary adenylate cyclase-activating polypeptide (PACAP) induces long-lasting nociceptive behaviors for more than 60 min in mice, while the involvement of PACAP type1 receptor (PAC₁-R) has not been clarified yet. The present study investigated signaling mechanisms of the PACAP-induced prolonged nociceptive behaviors. Single i.t. injection of a selective PAC₁-R agonist, maxadilan (Max), mimicked nociceptive behaviors in a dose-dependent manner similar to PACAP. Pre- or post-treatment of a selective PAC₁-R antagonist, max.d.4, significantly inhibited the nociceptive behaviors by PACAP or Max. Coadministration of a protein kinase A inhibitor, Rp-8-Br-cAMPS, a mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor, PD98059 or a c-Jun N-terminal kinase (JNK) inhibitor, SP600125, significantly inhibited the nociceptive behaviors by Max. Immunohistochemistry and immunoblotting analysis revealed that spinal administration of Max-induced ERK phosphorylation and JNK phosphorylation, and also augmented an astrocyte marker, glial fibrillary acidic protein in mouse spinal cord. Furthermore, an astroglial toxin, l-α-aminoadipate, significantly attenuated the development of the nociceptive behaviors and ERK phosphorylation by Max. These results suggest that the activation of spinal PAC₁-R induces long-lasting nociception through the interaction of neurons and astrocytes.
Stimulatory effect of pituitary adenylate cyclase-activating polypeptide 6-38, M65 and vasoactive intestinal polypeptide 6-28 on trigeminal sensory neurons
2015, Neuroscience
Pituitary adenylate cyclase-activating polypeptide (PACAP) acts on G protein-coupled receptors: the specific PAC1 and VPAC1/VPAC2 receptors. PACAP6-38 was described as a potent PAC1/VPAC2 antagonist in several models, but recent studies reported its agonistic behaviors proposing novel receptorial mechanisms. Since PACAP in migraine is an important research tool, we investigated the effect of PACAP and its peptide fragments on trigeminal primary sensory neurons.
Effect of the peptides was studied with ratiometric Ca-imaging technique using the fluorescent indicator fura-2 AM on primary cultures of rat and mouse trigeminal ganglia (TRGs) neurons. Specificity testing was performed on PAC1, VPAC1 and VPAC2 receptor-expressing cell lines with both fluorescent and radioactive Ca-uptake methods.
Slowly increasing intracellular free calcium concentration [Ca²⁺]_i was detected after PACAP1-38, PACAP1-27, vasoactive intestinal polypeptide (VIP) and the selective PAC1 receptor agonist maxadilan administration on TRG neurons, but interestingly, PACAP6-38, VIP6-28 and the PAC1 receptor antagonist M65 also caused similar activation. The VPAC2 receptor agonist BAY 55-9837 induced similar activation, while the VPAC1 receptor agonist Ala^11,22,28VIP had no significant effect on [Ca²⁺]_i. It was proven that the Ca²⁺-influx originated from intracellular stores using radioactive calcium-45 uptake experiment and Ca-free solution. On the specific receptor-expressing cell lines the antagonists inhibited the stimulating actions of the respective agonists, but had no effects by themselves.
PACAP6-38, M65 and VIP6-28, which were described as antagonists in numerous studies in several model systems, act as agonists on TRG primary sensory neurons. Currently unknown receptors or splice variants linked to distinct signal transduction pathways might explain these differences.

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Pituitary adenylate cyclase activating polypeptide expression in sensory neurons

Abstract

Biochim. biophys. Acta

Biochem. biophys. Res. Commun.

J. chem. Neuroanat.

Peptides

Biochem. biophys. Res. Commun.

Biochem. biophys. Res. Commun.

Neuroscience

Biochem. biophys. Res. Commun.

Neuroscience

Regul. Pept.

Neuroscience

Calcitonin/calcitonin gene related peptide transcription unit: tissue-specific expression involves selective use of alternative polyadenylation sites

Molec. Cell Biol.

Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes

Endocrinology