ADCYAP1R1

Official Full Name

ADCYAP receptor type I

Organism

Homo sapiens

GeneID

117

Background

This gene encodes type I adenylate cyclase activating polypeptide receptor, which is a membrane-associated protein and shares significant homology with members of the glucagon/secretin receptor family. This receptor mediates diverse biological actions of adenylate cyclase activating polypeptide 1 and is positively coupled to adenylate cyclase. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Dec 2010]

Synonyms

PAC1; PAC1R; PACAPR; PACAPRI;

Protein Sequence

MAGVVHVSLAALLLLPMAPAMHSDCIFKKEQAMCLEKIQRANELMGFNDSSPGCPGMWDNITCWKPAHVGEMVLVSCPELFRIFNPDQVWETETIGESDFGDSNSLDLSDMGVVSRNCTEDGWSEPFPHYFDACGFDEYESETGDQDYYYLSVKALYTVGYSTSLVTLTTAMVILCRFRKLHCTRNFIHMNLFVSFMLRAISVFIKDWILYAEQDSNHCFISTVECKAVMVFFHYCVVSNYFWLFIEGLYLFTLLVETFFPERRYFYWYTIIGWGTPTVCVTVWATLRLYFDDTGCWDMNDSTALWWVIKGPVVGSIMVNFVLFIGIIVILVQKLQSPDMGGNESSIYLRLARSTLLLIPLFGIHYTVFAFSPENVSKRERLVFELGLGSFQGFVVAVLYCFLNGEVQAEIKRKWRSWKVNRYFAVDFKHRHPSLASSGVNGGTQLSILSKSSSQIRMSGLPADNLAT

Open

Disease

Migraine, Pituitary gland disorder

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The ADCYAP1R1 gene encodes the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) receptor type I, which is essential to nervous system signaling. ADCYAP1R1's control of PACAP's various physiological effects is essential as a class B GPCR. Knowing the ADCYAP1R1's processes not only clarifies its biological relevance but also helps to place it as a potential target for therapy.

Gene Structure and Function

Two physiologically active versions of a receptor mostly activated by PACAP exist PACAP-27 and PACAP-38, and ADCYAP1R1 is in charge of encoding them. After post-translational processing of a precursor protein, these peptides result. Emphasizing its conserved function in cellular signaling, the receptor itself is a membrane-associated protein that has major similarities with other members of the glucagon/secretin receptor family.

G proteins, notably Gs and Gq, activate adenylyl cyclase and phospholipase C pathways to power the receptor. As cyclic AMP (cAMP) levels increase, inositol trisphosphate (IP3) and diacylglycerol (DAG) are generated, which regulate various physiological activities.

Mechanisms of Action

Two important signaling pathways are engaged by activation of the PAC1 receptor (ADCYAP1R1), therefore proving its vital function in physiological control. The adenylyl cyclase/cAMP pathway is triggered when PACAP attaches to ADCYAP1R1 via Gs proteins, hence raising cAMP levels. This increase in cAMP then promotes EPAC pathways and protein kinase A (PKA), which may cooperate to boost MEK/ERK signaling and hence affect a range of physiological responses including hormone release, neuronal excitability, and synaptic plasticity.

Concurrently, Gq proteins are triggered, therefore activating the phospholipase C pathway. Calcium ion release from the endoplasmic reticulum and activation of protein kinase C (PKC) follow from this enzyme catalyzing the synthesis of inositol trisphosphate (IP3) and diacylglycerol (DAG.). Smooth muscle contraction, secretion, and neural signaling all depend on this route in great part.

From endocrine actions to neuroprotective mechanisms, ADCYAP1R1's ability to activate many signaling pathways enables it to control a wide range of physiological processes. Moreover, PAC1R activation results in the recruitment of β-arrestin, thus enabling receptor internalization and the building of endosomal signaling platforms supporting long-term MEK/ERK signaling, thus prolonging their impact on cellular dynamics.

Figure 1 describes the activation mechanism of PAC1R signaling cascades and their impact on MEK/ERK signaling. Figure 1. A schematic of PAC1R signaling cascades. (Liao C, et al., 2019)

Physiological Roles of PACAP and ADCYAP1R1

Different biological effects of PACAP and its receptor ADCYAP1R1 are observed in many systems. PACAP is known in the central nervous system (CNS) for its neuroprotective qualities, which encourage cell survival and help to reduce death under stress. Given neurodegenerative illnesses, where PACAP signaling can help offset cellular damage linked with disorders like Alzheimer's and Parkinson's diseases, this is particularly important.

Furthermore important for reproductive physiology, especially in spermatogenesis and sperm motility, ADCYAP1R1 The receptor emphasizes its many functions in both central and peripheral tissues as it helps smooth muscle relaxation and secretion in the gastrointestinal system.

Normal physiology depends on ADCYAP1R1, although disruption of PACAP signaling has been associated with many diseases. Conditions connected to stress, like depression and post-traumatic stress disorder (PTSD), may be exacerbated by too strong PACAP signals. On the other hand, insufficient receptor activation could cause metabolic diseases like diabetes and obesity as well as chronic pain syndromes. These links show the possibility of ADCYAP1R1 as a therapeutic target; modification of its activity might provide paths for treating many diseases.

Therapeutic Targeting of ADCYAP1R1

ADCYAP1R1 offers a convincing target for therapeutic development given the role of the receptor in several physiological and pathological events. The development of peptide-based and small-molecule therapies that specifically control PACAP signaling has received much attention recently. Nevertheless, the rational design of these molecules suffers from the absence of thorough structural knowledge of the active state of the receptor.

Discovering the molecular connections between PACAP and ADCYAP1R1 can help to create more targeted and efficient treatments, hence research efforts are directed more and more toward this goal. Designing treatments that may either increase or decrease receptor activity depends on the therapeutic environment; so, knowledge of the activation mechanisms and signaling pathways of the receptor will be absolutely vital.

References:

Liao C, de Molliens MP, Schneebeli ST, et al. Targeting the PAC1 Receptor for Neurological and Metabolic Disorders. Curr Top Med Chem. 2019;19(16):1399-1417.
Liao C, May V, Li J. PAC1 Receptors: Shapeshifters in Motion. J Mol Neurosci. 2019;68(3):331-339.
May V, Johnson GC, Hammack SE, et al. PAC1 Receptor Internalization and Endosomal MEK/ERK Activation Is Essential for PACAP-Mediated Neuronal Excitability. J Mol Neurosci. 2021;71(8):1536-1542. doi:10.1007/s12031-021-01821-x

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