Discovery of PACAP and its receptors in the brain

Hirabayashi, Takahiro; Nakamachi, Tomoya; Shioda, Seiji

doi:10.1186/s10194-018-0855-1

Cited by 110 publications

(88 citation statements)

References 77 publications

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“…The PAC1 receptor also triggers the activation of several other protein kinase cascades such as ERK1/2, JNK1/2, p38 MAPK and PKB [ 41 , 42 , 43 ]. Consequently, N2a cells have the ability to bind the pituitary adenylate cyclase-activating polypeptide (PACAP), which is widely distributed in the brain and peripheral organs and displays high affinity for the PAC1 receptor [ 40 , 44 ]. They can also be used to study other neuropeptides or molecules (natural or synthetic) capable of interacting with receptors of the GPCR superfamily.…”

Section: Introductionmentioning

confidence: 99%

Induction of Neuronal Differentiation of Murine N2a Cells by Two Polyphenols Present in the Mediterranean Diet Mimicking Neurotrophins Activities: Resveratrol and Apigenin

et al. 2018

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In the prevention of neurodegeneration associated with aging and neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease), neuronal differentiation is of interest. In this context, neurotrophic factors are a family of peptides capable of promoting the growth, survival, and/or differentiation of both developing and immature neurons. In contrast to these peptidyl compounds, polyphenols are not degraded in the intestinal tract and are able to cross the blood–brain barrier. Consequently, they could potentially be used as therapeutic agents in neurodegenerative pathologies associated with neuronal loss, thus requiring the stimulation of neurogenesis. We therefore studied the ability to induce neuronal differentiation of two major polyphenols present in the Mediterranean diet: resveratrol (RSV), a major compound found in grapes and red wine, and apigenin (API), present in parsley, rosemary, olive oil, and honey. The effects of these compounds (RSV and API: 6.25–50 µM) were studied on murine neuro-2a (N2a) cells after 48 h of treatment without or with 10% fetal bovine serum (FBS). Retinoic acid (RA: 6.25–50 µM) was used as positive control. Neuronal differentiation was morphologically evaluated through the presence of dendrites and axons. Cell growth was determined by cell counting and cell viability by staining with fluorescein diacetate (FDA). Neuronal differentiation was more efficient in the absence of serum than with 10% FBS or 10% delipidized FBS. At concentrations inducing neuronal differentiation, no or slight cytotoxicity was observed with RSV and API, whereas RA was cytotoxic. Without FBS, RSV and API, as well as RA, trigger the neuronal differentiation of N2a cells via signaling pathways simultaneously involving protein kinase A (PKA)/phospholipase C (PLC)/protein kinase C (PKC) and MEK/ERK. With 10% FBS, RSV and RA induce neuronal differentiation via PLC/PKC and PKA/PLC/PKC, respectively. With 10% FBS, PKA and PLC/PKC as well as MEK/ERK signaling pathways were not activated in API-induced neuronal differentiation. In addition, the differentiating effects of RSV and API were not inhibited by cyclo[DLeu5] OP, an antagonist of octadecaneuropeptide (ODN) which is a neurotrophic factor. Moreover, RSV and API do not stimulate the expression of the diazepam-binding inhibitor (DBI), the precursor of ODN. Thus, RSV and API are able to induce neuronal differentiation, ODN and its receptor are not involved in this process, and the activation of the (PLC/PKC) signaling pathway is required, except with apigenin in the presence of 10% FBS. These data show that RSV and API are able to induce neuronal differentiation and therefore mimic neurotrophin activity. Thus, RSV and API could be of interest in regenerative medicine to favor neurogenesis.

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Section: Introductionmentioning

confidence: 99%

Induction of Neuronal Differentiation of Murine N2a Cells by Two Polyphenols Present in the Mediterranean Diet Mimicking Neurotrophins Activities: Resveratrol and Apigenin

et al. 2018

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“…VPAC1 and VPAC2 are more related to peripheral actions and are equally recognized by both PACAP and VIP [13]. PACAP plays a very important role in brain development and is widely expressed in the embryonic brain at the onset of neurogenesis [14,15]. After the termination of brain development, PACAP expression is reduced in most brain areas [16].…”

Section: General Overviewmentioning

confidence: 99%

The Neuroprotective and Biomarker Potential of PACAP in Human Traumatic Brain Injury

Tóth

Tamás

Reglődi

2020

IJMS

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Traumatic brain injury remains a growing public health concern and represents the greatest contributor to death and disability globally among all trauma-related injuries. There are limited clinical data regarding biomarkers in the diagnosis and outcome prediction of TBI. The lack of real effective treatment for recovery calls for research of TBI to be shifted into the area of prevention, treatment of secondary brain injury and neurorehabilitation. The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has been reported to act as a hormone, a neuromodulator, a neurotransmitter and a trophic factor, and has been implicated in a variety of developmental and regenerative processes. The importance of PACAP in neuronal regeneration lies in the upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central nervous system injury. The aim of this minireview is to summarize both the therapeutic and biomarker potential of the neuropeptide PACAP, as a novel possible target molecule presently being investigated in several human conditions including TBI, and with encouraging results in animal models of TBI.

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“…We first tested whether stimulation of PAC1R signaling and enhanced proteasome activity by PACAP can lead to reduced misfolding of endogenous tau upon exposure to tau seeds in primary neuronal cultures from the PS19 tau transgenic line that encodes the P301S tau mutation. After being released from axon terminals, PACAP exerts its physiologic function by binding to, and stimulating PAC1R, a Gs-coupled GPCR, primarily located on post-synaptic membranes of neurons leading to potent activation of cAMP/PKA signaling (58,59). Through these intracellular signaling pathways, PACAP promotes neurogenesis and differentiation during neurodevelopment (86,87), inhibits apoptosis (88,89) and provides neuroprotection (60,(90)(91)(92) under various toxic stimuli in the developed brain.…”

Section: Pacap Can Attenuate Seed-induced Misfolding Of Endogenous Taumentioning

confidence: 99%

“…slow synaptic transmission by modulating the release and binding of neurotransmitters (55-57) are situated on the pre and post-synaptic terminals (55) and can propagate signal transduction restricted to synapses.In our study, we tested whether stimulation of pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R), a Gs-coupled GPCR, present on the membrane of the post-synaptic compartment can stimulate cAMP/PKA/proteasome tau degradation predominantly in the post-synaptic compartment. In the brain, PAC1R is stimulated by its ligand PACAP, which acts as a neurotransmitter, neurotrophic factor, and a neurohormone (58,59). Its effect on cell survival is mediated through stimulation of AC/cAMP/PKA signaling (60).…”

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confidence: 99%

GPCR-mediated clearance of tau in post-synaptic compartments attenuates tau pathologyin vivo

Schaler

Runyan

Fowler

et al. 2020

Preprint

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Accumulation of pathological tau in synapses has been identified as an early pathogenic event in Alzheimer's disease (AD) and correlates strongly with cognitive decline in patients with AD. Tau is a cytosolic, axonal protein. However, in the disease condition, tau accumulates in post-synaptic compartments and pre-synaptic terminals, either due to missorting within neurons, trans-synaptic transfer between neurons or due to failure of clearance systems in synapses. Using a sub-cellular fractionation assay, we show that progressive deposition of seed competent tau occurs predominantly in post-synaptic compartments in a tau transgenic mouse and in AD patient brain, making these neuronal structures particularly vulnerable to tau toxicity. Tau-mediated post-synaptic toxicity could be further exacerbated by impaired proteasome activity which we detected by measuring the levels of polyubiquitin chains that target proteins to proteasomal degradation. To combat the accumulation of tau and proteasome impairment at the subcellular level, we devised a therapeutic strategy of proteasome-mediated clearance of tau restricted to the post-synaptic compartment. Utilizing the pharmacology of GPCRs, we show that in vivo stimulation of the PAC1R receptor by its ligand can propagate intracellular PKA signaling leading to enhanced synaptic proteasome activity and reduced tau in the post-synaptic compartment. Over time, clearance of postsynaptic tau led to reduced tauopathy and cognitive decline in rTg4510 mice. Together, these results highlight a novel therapeutic strategy of targeting GPCRs that propagate cAMP/PKA signaling as a tool to activate proteolysis restricted to synapses to prevent the accumulation of tau in the early stages of AD. slow synaptic transmission by modulating the release and binding of neurotransmitters (55-57) are situated on the pre and post-synaptic terminals (55) and can propagate signal transduction restricted to synapses.In our study, we tested whether stimulation of pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R), a Gs-coupled GPCR, present on the membrane of the post-synaptic compartment can stimulate cAMP/PKA/proteasome tau degradation predominantly in the post-synaptic compartment. In the brain, PAC1R is stimulated by its ligand PACAP, which acts as a neurotransmitter, neurotrophic factor, and a neurohormone (58,59). Its effect on cell survival is mediated through stimulation of AC/cAMP/PKA signaling (60). In mammals, two biologically active forms of PACAP have been identified. The predominant form in CNS is PACAP38, composed of 38 amino acids, and the minor form is PACAP27, composed of the first 27 amino acids of PACAP38 (59). In this study, the subcellular characterization of tau species across different stages of tauopathy in rTg4510 mice and post-mortem tissue from AD patients shows that post-synaptic compartments are highly vulnerable to tau pathology due to accumulation of seed competent, high molecular weight (HMW), AT8 positive tau forms. Moreover, the chronic s...

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Discovery of PACAP and its receptors in the brain

Cited by 110 publications

References 77 publications

Induction of Neuronal Differentiation of Murine N2a Cells by Two Polyphenols Present in the Mediterranean Diet Mimicking Neurotrophins Activities: Resveratrol and Apigenin

Induction of Neuronal Differentiation of Murine N2a Cells by Two Polyphenols Present in the Mediterranean Diet Mimicking Neurotrophins Activities: Resveratrol and Apigenin

The Neuroprotective and Biomarker Potential of PACAP in Human Traumatic Brain Injury

GPCR-mediated clearance of tau in post-synaptic compartments attenuates tau pathologyin vivo

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