The Role of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Signaling in the Hippocampal Dentate Gyrus

Johnson, Gregory C; Parsons, Rodney L.; May, Víctor; Hammack, Sayamwong E.

doi:10.3389/fncel.2020.00111

Cited by 27 publications

(26 citation statements)

References 81 publications

(108 reference statements)

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“…PACAP polypeptides are produced throughout the brain where they act as neurotransmitters and also have neurotrophic effects. These peptides are released by both neurons and astrocytes during activity and thus PACAP accumulation in the paravascular space could feasibly activate pericyte G s -coupled PAC 1 receptors (Johnson et al, 2020), warranting further exploration of their potential involvement in NVC.…”

Section: The G S Receptor Complement Of Pericytes Suggest a Range Of mentioning

confidence: 99%

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Hariharan

Weir

Robertson

et al. 2020

Front. Cell. Neurosci.

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Brain pericytes reside on the abluminal surface of capillaries, and their processes cover ~90% of the length of the capillary bed. These cells were first described almost 150 years ago (Eberth, 1871; Rouget, 1873) and have been the subject of intense experimental scrutiny in recent years, but their physiological roles remain uncertain and little is known of the complement of signaling elements that they employ to carry out their functions. In this review, we synthesize functional data with single-cell RNAseq screens to explore the ion channel and G protein-coupled receptor (GPCR) toolkit of mesh and thin-strand pericytes of the brain, with the aim of providing a framework for deeper explorations of the molecular mechanisms that govern pericyte physiology. We argue that their complement of channels and receptors ideally positions capillary pericytes to play a central role in adapting blood flow to meet the challenge of satisfying neuronal energy requirements from deep within the capillary bed, by enabling dynamic regulation of their membrane potential to influence the electrical output of the cell. In particular, we outline how genetic and functional evidence suggest an important role for Gs-coupled GPCRs and ATP-sensitive potassium (KATP) channels in this context. We put forth a predictive model for long-range hyperpolarizing electrical signaling from pericytes to upstream arterioles, and detail the TRP and Ca2+ channels and Gq, Gi/o, and G12/13 signaling processes that counterbalance this. We underscore critical questions that need to be addressed to further advance our understanding of the signaling topology of capillary pericytes, and how this contributes to their physiological roles and their dysfunction in disease.

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Section: The G S Receptor Complement Of Pericytes Suggest a Range Of mentioning

confidence: 99%

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Hariharan

Weir

Robertson

et al. 2020

Front. Cell. Neurosci.

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“…Moreover, we and others have investigated the involvement of PACAP in multiple behaviors in animals and in human disease by performing phenotype analyses of PACAP-deficient mice and genetic linkage analyses in humans. For example, PACAP-knockout mice exhibit increased locomotor activity, anxiety/anxolytic phenotypes, depression-like behavior, deficits in learning and memory, cognitive impairment (Hashimoto et al, 2001(Hashimoto et al, , 2009Tanaka et al, 2006;Ishihama et al, 2010;Hattori et al, 2012; for reviews see: Hammack and May, 2015;Mustafa et al, 2015;Shibasaki et al, 2015;Farkas et al, 2017;Missig et al, 2017;Reglodi et al, 2018b;Johnson et al, 2020). Of note, the behavioral phenotype of PACAPknockout mice varies under different environmental conditions and different genetic backgrounds (mouse strain), and with the specific gene sequences that were deleted in the different PACAP gene knockout models.…”

Section: Introductionmentioning

confidence: 99%

Probing the VIPR2 Microduplication Linkage to Schizophrenia in Animal and Cellular Models

et al. 2021

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Pituitary adenylate cyclase-activating polypeptide (PACAP, gene name ADCYAP1) is a multifunctional neuropeptide involved in brain development and synaptic plasticity. With respect to PACAP function, most attention has been given to that mediated by its specific receptor PAC1 (ADCYAP1R1). However, PACAP also binds tightly to the high affinity receptors for vasoactive intestinal peptide (VIP, VIP), called VPAC1 and VPAC2 (VIPR1 and VIPR2, respectively). Depending on innervation patterns, PACAP can thus interact physiologically with any of these receptors. VPAC2 receptors, the focus of this review, are known to have a pivotal role in regulating circadian rhythms and to affect multiple other processes in the brain, including those involved in fear cognition. Accumulating evidence in human genetics indicates that microduplications at 7q36.3, containing VIPR2 gene, are linked to schizophrenia and possibly autism spectrum disorder. Although detailed molecular mechanisms have not been fully elucidated, recent studies in animal models suggest that overactivation of the VPAC2 receptor disrupts cortical circuit maturation. The VIPR2 linkage can thus be potentially explained by inappropriate control of receptor signaling at a time when neural circuits involved in cognition and social behavior are being established. Alternatively, or in addition, VPAC2 receptor overactivity may disrupt ongoing synaptic plasticity during processes of learning and memory. Finally, in vitro data indicate that PACAP and VIP have differential activities on the maturation of neurons via their distinct signaling pathways. Thus perturbations in the balance of VPAC2, VPAC1, and PAC1 receptors and their ligands may have important consequences in brain development and plasticity.

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“…High levels of PAC1 receptor transcripts in the granule cell layer of the dentate gyrus in the hippocampus were initially determined by in situ hybridization studies (Jaworski and Proctor, 2000;Hannibal, 2002) and hippocampal PACAP hilar mossy neurons were shown to send fiber projections to the DG inner molecular layer (IML) (Condro et al, 2016;Johnson et al, 2020b); hence, there are short PACAPergic synaptic circuits between PACAP-expressing hilar mossy cells and the proximal dendrites on PAC1 receptor expressing DG granule cells. Accordingly, PACAP application to hippocampal dentate gyrus slice preparations increased the excitability of granule cells (Johnson et al, 2020a;Johnson et al, 2020b). In whole-cell recordings in current clamp mode, the granule cells fired tonically in response to suprathreshold 1 second depolarizing current injections; the action potential frequency increased with increasing current intensity (Johnson et al, 2020a;Johnson et al, 2020b).…”

Section: Pacap Increases Granule Cell Excitability Through Endosomal Erk Activationmentioning

confidence: 99%

PAC1 Receptor Internalization and Endosomal MEK/ERK Activation Is Essential for PACAP-Mediated Neuronal Excitability

et al. 2021

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Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) activation of PAC1 receptors (Adcyap1r1) can significantly increase the excitability of diverse neurons through differential mechanisms. For guinea pig cardiac neurons, the modulation of excitability can be mediated in part by PAC1 receptor plasma membrane G protein-dependent activation of adenylyl cyclase and downstream signaling cascades. By contrast, PAC1 receptor-mediated excitability of hippocampal dentate gyrus granule cells appears independent of membrane delimited AC/cAMP/PKA and PLC/PKC signaling. For both neuronal types, there is mechanistic convergence demonstrating that endosomal PAC1 receptor signaling has prominent roles. In these models, neuronal exposure to Pitstop2 to inhibit β-arrestin/clathrin-mediated PAC1 receptor internalization eliminates PACAP modulation of excitability. β-arrestin is a scaffold for a number of effectors especially MEK/ERK and notably, paradigms that inhibit PAC1 receptor endosome formation and ERK signaling also blunt the PACAP-induced increase in excitability. Detailed PAC1 receptor internalization and endosomal ERK signaling mechanisms have been confirmed in HEK PAC1R-EGFP cells and shown to be long lasting which appear to recapitulate the sustained electrophysiological responses. Thus, PAC1 receptor internalization/endosomal recruitment efficiently and efficaciously activates MEK/ERK signaling and appears to represent a singular and critical common denominator in regulating neuronal excitability by PACAP.

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The Role of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Signaling in the Hippocampal Dentate Gyrus

Cited by 27 publications

References 81 publications

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Probing the VIPR2 Microduplication Linkage to Schizophrenia in Animal and Cellular Models

PAC1 Receptor Internalization and Endosomal MEK/ERK Activation Is Essential for PACAP-Mediated Neuronal Excitability

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