Abstract:Pituitary adenylate cyclase activating polypeptide acting through its cognate receptors, PAC1, VPAC1, and VPAC2, is a pleiotropic signaling neuropeptide of the vasoactive intestinal peptide/secretin/glucagon family. PACAP has known functions in neuronal growth, development, repair, and central PACAP signaling has acute behavioral consequences. One of the ways in which PACAP may affect neuronal function is through the modulation of intrinsic membrane currents to control neuronal excitability. Here we review evi… Show more
“…Activity-dependent regulation of both glutamate and GABA vesicular transporter synthesis and membrane insertion has been reported (De Gois, Schafer et al 2005, Erickson, De Gois et al 2006, Doyle, Pyndiah et al 2010. PACAP signaling most commonly leads to a net increase in neuronal excitability through modulation of intrinsic membrane currents and transiently increasing intracellular calcium concentration (Johnson, May et al 2019). Decreased vesicular transporter mRNA expression would be expected at the cellular level to decrease transmitter quantal size, thus decreasing excitatory/inhibitory postsynaptic currents (EPSCs and IPSCs respectively) (Billups 2005), and is consistent with our behavior data.…”
Section: Figure 8 Continuedsupporting
confidence: 90%
“…PACAP binding to PAC1 receptors initiates signaling through multiple intracellular pathways. PACAP/PAC1 signaling is generally considered to engage Gαs, activating adenylate cyclase, and Gαq, activating phospholipase C, and leads to multiple cellular responses including increased neuronal excitability (Kawasaki, Springett et al 1998, Emery, Eiden et al 2013, Jiang, Xu et al 2017, Johnson, May et al 2019. The PACAP/PAC1 signaling pathway has consistently been related to psychogenic stress responding, and potentiation of this pathway has been linked to psychopathologies including anxiety and PTSD in human (Ressler, Mercer et al 2011, Wang, Cao et al 2013, Mustafa, Jiang et al 2015.…”
The neuropeptide PACAP, acting as a co-transmitter, increases neuronal excitability, which may enhance anxiety and arousal associated with threat conveyed by multiple sensory modalities. The distribution of neurons expressing PACAP and its receptor, PAC1, throughout the mouse nervous system was determined, in register with expression of glutamatergic and GABAergic neuronal markers, to develop a coherent chemoanatomical picture of PACAP role in brain motor responses to sensory input. A circuit role for PACAP was tested by observing fos activation of brain neurons after olfactory threat cue in wild type and PACAP knockout mice. Neuronal activation, and behavioral response, were blunted in PACAP knock-out mice, accompanied by sharply down-regulated vesicular transporter expression in both GABAergic and glutamatergic neurons expressing PACAP and its receptor. This report signals a new perspective on the role of neuropeptide signaling in supporting excitatory and inhibitory neurotransmission in the nervous system within functionally coherent polysynaptic circuits.
“…Activity-dependent regulation of both glutamate and GABA vesicular transporter synthesis and membrane insertion has been reported (De Gois, Schafer et al 2005, Erickson, De Gois et al 2006, Doyle, Pyndiah et al 2010. PACAP signaling most commonly leads to a net increase in neuronal excitability through modulation of intrinsic membrane currents and transiently increasing intracellular calcium concentration (Johnson, May et al 2019). Decreased vesicular transporter mRNA expression would be expected at the cellular level to decrease transmitter quantal size, thus decreasing excitatory/inhibitory postsynaptic currents (EPSCs and IPSCs respectively) (Billups 2005), and is consistent with our behavior data.…”
Section: Figure 8 Continuedsupporting
confidence: 90%
“…PACAP binding to PAC1 receptors initiates signaling through multiple intracellular pathways. PACAP/PAC1 signaling is generally considered to engage Gαs, activating adenylate cyclase, and Gαq, activating phospholipase C, and leads to multiple cellular responses including increased neuronal excitability (Kawasaki, Springett et al 1998, Emery, Eiden et al 2013, Jiang, Xu et al 2017, Johnson, May et al 2019. The PACAP/PAC1 signaling pathway has consistently been related to psychogenic stress responding, and potentiation of this pathway has been linked to psychopathologies including anxiety and PTSD in human (Ressler, Mercer et al 2011, Wang, Cao et al 2013, Mustafa, Jiang et al 2015.…”
The neuropeptide PACAP, acting as a co-transmitter, increases neuronal excitability, which may enhance anxiety and arousal associated with threat conveyed by multiple sensory modalities. The distribution of neurons expressing PACAP and its receptor, PAC1, throughout the mouse nervous system was determined, in register with expression of glutamatergic and GABAergic neuronal markers, to develop a coherent chemoanatomical picture of PACAP role in brain motor responses to sensory input. A circuit role for PACAP was tested by observing fos activation of brain neurons after olfactory threat cue in wild type and PACAP knockout mice. Neuronal activation, and behavioral response, were blunted in PACAP knock-out mice, accompanied by sharply down-regulated vesicular transporter expression in both GABAergic and glutamatergic neurons expressing PACAP and its receptor. This report signals a new perspective on the role of neuropeptide signaling in supporting excitatory and inhibitory neurotransmission in the nervous system within functionally coherent polysynaptic circuits.
“…PACAP is an important neurotransmitter peripherally, in both the sympathetic and parasympathetic branches of the autonomic nervous system, and in the brain mediates hedonic tone, anxiety, and sociability as a function of stress. Hammack and colleagues summarize the cellular actions of PACAP in cholinergic preganglionic neurons, and elsewhere, at the level of intrinsic ion channel regulation. Their pithy summary of these effects is noteworthy, as these may be paradigmatic for the actions of other peptides at the cellular level.…”
Section: Pacap—a Neuropeptide With Broad Homeo‐ and Allostatic Rolesmentioning
confidence: 99%
“…Although most peptides are notable as hormone and transmitter secretagogues, they mediate secretion and other cellular actions, including gene regulation, via mechanisms quite distinct from ionotropic receptors. Rather than directly regulating the open and closed states of ion channels in excitable cells, PACAP, like many other peptide GPCRs, affects ion channel function metabotropically, that is, via intracellular mechanisms rather than direct “gating” of the channels themselves . This provides a completely different time scale to peptide effects on excitability, and one that must be considered in the context of the “primary” regulators of excitability, such as acetylcholine in the mammalian peripheral nervous system, and acetylcholine and glutamate in the mammalian central nervous system.…”
Section: Pacap—a Neuropeptide With Broad Homeo‐ and Allostatic Rolesmentioning
The field of regulatory peptide research has developed significant momentum owing to several recent converging trends. Dozens of peptide-based drugs have been approved by the U.S. Food and Drug Administration in the past decade, the majority for the treatment of metabolic disorders, including diabetes. These are the "tip of the spear" for peptide therapeutics, revealing that impediments of delivery, stability, and bioavailability inherent in peptide drugs have in many cases been overcome. While most are orally available, and directed at peripheral targets, pharmaceutical delivery of peptides to the central nervous system through nasal mucosal routes has also seen much progress. Cell-based high-throughput drug discovery methods, the X-ray crystallographic structural definition of G proteincoupled receptors, and deorphanization of peptide-liganded receptors have contributed to the emergence of new targets for pharmacological intervention and accelerated the development of peptide-based as well as nonpeptide congeners for existing ones. Finally, the recognition that peptides act at their receptors, in a cellular context, in conjunction with other peptides and other first messengers, including neurotransmitters, hormones, and autocrine and paracrine factors, has led to an increased appreciation for the combinatorial possibilities of regulatory peptide action, now penetrating to drug design and discovery efforts. The fifteen reviews, reports, and perspectives collected in this special issue of Annals of the New York Academy of Sciences provide a snapshot of the frontiers of the field of regulatory peptide research as they expand physiologically, pharmacologically, and therapeutically.
“…PACAP binding to its receptors Vipr1, Vipr2 and, predominantly, PAC1 initiates cell signaling through multiple intracellular pathways ( Harmar, 2001 ). PACAP acting at PAC1 is generally considered to engage Gαs, activating adenylate cyclase, with some isoforms also activating phospholipase C via Gαq, leading to multiple cellular responses including increased neuronal excitability ( Pisegna and Wank, 1993 ; Spengler et al, 1993 ; Kawasaki et al, 1998 ; Emery et al, 2013 ; Jiang et al, 2017 ; Johnson et al, 2019 ). The PACAP/PAC1 signaling pathway has consistently been related to psychogenic stress responding, and potentiation of this pathway has been linked to psychopathologies including anxiety and PTSD in human ( Ressler et al, 2011 ; Wang et al, 2013a ; Mustafa et al, 2015 ).…”
The neuropeptide PACAP, acting as a co-transmitter, increases neuronal excitability, which may enhance anxiety and arousal associated with threat conveyed by multiple sensory modalities. The distribution of neurons expressing PACAP and its receptor, PAC1, throughout the mouse nervous system was determined, in register with expression of glutamatergic and GABAergic neuronal markers, to develop a coherent chemoanatomical picture of PACAP role in brain motor responses to sensory input. A circuit role for PACAP was tested by observing fos activation of brain neurons after olfactory threat cue in wild type and PACAP knockout mice. Neuronal activation, and behavioral response, were blunted in PACAP knock-out mice, accompanied by sharply down-regulated vesicular transporter expression in both GABAergic and glutamatergic neurons expressing PACAP and its receptor. This report signals a new perspective on the role of neuropeptide signaling in supporting excitatory and inhibitory neurotransmission in the nervous system within functionally coherent polysynaptic circuits.
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