Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors

Lu, Jessica Bo Li; Piper, Sarah; Zhao, Peishen; Miller, Laurence J.; Wootten, Denise; Sexton, Patrick M.

doi:10.3390/ijms23158069

Cited by 16 publications

(13 citation statements)

References 348 publications

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“…The crosstalk between glucose metabolism status and the anti-inflammatory power of the vagus nerve could be mediated by neuropeptides [ 61 ]—in particular by vasoactive intestinal peptide (VIP), along with its receptors and downstream pathway (see [ 62 ] for a recent review). Indeed, VIP is released upon vagus nerve stimulation (VNS) [ 63 ], is synthesized in the gut, the brain, and the vagus nerve [ 64 ], and can be co-transmitted with acetylcholine—most notably in exocrine glands [ 65 ].…”

Section: The Vagus Nerve Seems Essential To Neuroimmunometabolism And...mentioning

confidence: 99%

Understanding the Pivotal Role of the Vagus Nerve in Health from Pandemics

Rangon¹,

Niezgoda

2022

Bioengineering

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The COVID-19 pandemic seems endless with the regular emergence of new variants. Is the SARS-CoV-2 virus particularly evasive to the immune system, or is it merely disrupting communication between the body and the brain, thus pre-empting homeostasis? Retrospective analysis of the COVID-19 and AIDS pandemics, as well as prion disease, emphasizes the pivotal but little-known role of the 10th cranial nerve in health. Considering neuroimmunometabolism from the point of view of the vagus nerve, non-invasive bioengineering solutions aiming at monitoring and stimulating the vagal tone are subsequently discussed as the next optimal and global preventive treatments, far beyond pandemics.

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Section: The Vagus Nerve Seems Essential To Neuroimmunometabolism And...mentioning

confidence: 99%

Understanding the Pivotal Role of the Vagus Nerve in Health from Pandemics

Rangon¹,

Niezgoda

2022

Bioengineering

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“…Pituitary adenylate cyclase‐activating peptide (PACAP), encoded in mouse by the gene Adcyap1 , is a member of the glucagon‐secretin‐vasoactive intestinal polypeptide superfamily 1 . PACAP can act as a neurotransmitter, neuromodulator and neurotrophic factor, 2–6 and is a high‐affinity ligand for three related G‐protein coupled receptors linked to Gs; PAC1, VPAC1 and VPAC2 7–10 . PACAP's putative physiological roles in adult mammals as revealed in PACAP‐deficient mice are most closely phenocopied by PAC1‐deficiency 11 .…”

Section: Introductionmentioning

confidence: 99%

Constitutive and conditional deletion reveals distinct phenotypes driven by developmental versus neurotransmitter actions of the neuropeptide PACAP

Bakalar

Гаврилова

Jiang

et al. 2023

J Neuroendocrinology

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Neuropeptides may exert trophic effects during development, and then neurotransmitter roles in the developed nervous system. One way to associate peptide‐deficiency phenotypes with either role is first to assess potential phenotypes in so‐called constitutive knockout mice, and then proceed to specify, regionally and temporally, where and when neuropeptide expression is required to prevent these phenotypes. We have previously demonstrated that the well‐known constellation of behavioral and metabolic phenotypes associated with constitutive pituitary adenylate cyclase‐activating peptide (PACAP) knockout mice are accompanied by transcriptomic alterations of two types: those that distinguish the PACAP‐null phenotype from wild‐type (WT) in otherwise quiescent mice (cPRGs), and gene induction that occurs in response to acute environmental perturbation in WT mice that do not occur in knockout mice (aPRGs). Comparing constitutive PACAP knockout mice to a variety of temporally and regionally specific PACAP knockouts, we show that the prominent hyperlocomotor phenotype is a consequence of early loss of PACAP expression, is associated with Fos overexpression in hippocampus and basal ganglia, and that a thermoregulatory effect previously shown to be mediated by PACAP‐expressing neurons of medial preoptic hypothalamus is independent of PACAP expression in those neurons in adult mice. In contrast, PACAP dependence of weight loss/hypophagia triggered by restraint stress, seen in constitutive PACAP knockout mice, is phenocopied in mice in which PACAP is deleted after neuronal differentiation. Our results imply that PACAP has a prominent role as a trophic factor early in development determining global central nervous system characteristics, and in addition a second, discrete set of functions as a neurotransmitter in the fully developed nervous system that support physiological and psychological responses to stress.

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“…Due to their wide distribution and functions, these receptors have the potential to be leveraged as therapeutic targets. However, their considerable structural homology has hindered the development of immunological tools, as well as potent, selective, and stable ligands, making the identification of the specific receptor subtype responsible for various physiological and pathological processes difficult 12 . The use of transgenic mice lacking these peptides or receptors has offered an alternative way to study the PACAP/VIP systems 6,13 .…”

Section: Introductionmentioning

confidence: 99%

“…However, their considerable structural homology has hindered the development of immunological tools, as well as potent, selective, and stable ligands, making the identification of the specific receptor subtype responsible for various physiological and pathological processes difficult. 12 The use of transgenic mice lacking these peptides or receptors has offered an alternative way to study the PACAP/VIP systems. 6,13 For example, such models have allowed elucidation of the role of PAC1R in the insulinotropic response to glucose 14 and of VIP and VPAC2R in circadian rhythm.…”

Section: Introductionmentioning

confidence: 99%

Gene deletion of the PACAP/VIP receptor, VPAC2R, alters glycemic responses during metabolic and psychogenic stress in adult female mice

Kozlova,

Bishay,

Denys

et al. 2023

J Neuroendocrinology

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Pituitary adenylate cyclase‐activating polypeptide (PACAP) and the homologous peptide, vasoactive intestinal peptide (VIP), participate in glucose homeostasis using insulinotropic and counterregulatory processes. The role of VIP receptor 2 (VPAC2R) in these opposing actions needs further characterization. In this study, we examined the participation of VPAC2R on basal glycemia, fasted levels of glucoregulatory hormones and on glycemia responses during metabolic and psychogenic stress using gene‐deleted (Vipr2−/−) female mice. The mean basal glycemia was significantly greater in Vipr2−/− in the fed state and after an 8‐h overnight fast as compared to wild‐type (WT) mice. Insulin tolerance testing following a 5‐h fast (morning fast, 0.38 U/kg insulin) indicated no effect of genotype. However, during a more intense metabolic challenge (8 h, ON fast, 0.25 U/kg insulin), Vipr2−/− females displayed significantly impaired insulin hypoglycemia. During immobilization stress, the hyperglycemic response and plasma epinephrine levels were significantly elevated above basal in Vipr2−/−, but not WT mice, in spite of similar stress levels of plasma corticosterone. Together, these results implicate participation of VPAC2R in upregulated counterregulatory processes influenced by enhanced sympathoexcitation. Moreover, the suppression of plasma GLP‐1 levels in Vipr2−/− mice may have removed the inhibition on hepatic glucose production and the promotion of glucose disposal by GLP‐1. qPCR analysis indicated deregulation of central gene markers of PACAP/VIP signaling in Vipr2−/−, upregulated medulla tyrosine hydroxylase (Th) and downregulated hypothalamic Vip transcripts. These results demonstrate a physiological role for VPAC2R in glucose metabolism, especially during insulin challenge and psychogenic stress, likely involving the participation of sympathoadrenal activity and/or metabolic hormones.

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Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors

Cited by 16 publications

References 348 publications

Understanding the Pivotal Role of the Vagus Nerve in Health from Pandemics

Understanding the Pivotal Role of the Vagus Nerve in Health from Pandemics

Constitutive and conditional deletion reveals distinct phenotypes driven by developmental versus neurotransmitter actions of the neuropeptide PACAP

Gene deletion of the PACAP/VIP receptor, VPAC2R, alters glycemic responses during metabolic and psychogenic stress in adult female mice

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