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更新于：2025-05-07

ADCYAP1R1

更新于：2025-05-07

基本信息

别名

ADCYAP receptor type I、ADCYAP1R1、adenylate cyclase activating polypeptide 1 (pituitary) receptor type I

+ [10]

简介

G protein-coupled receptor activated by the neuropeptide pituitary adenylate cyclase-activating polypeptide (ADCYAP1/PACAP) (PubMed:32047270, PubMed:33715378, PubMed:35477937, PubMed:36385145). Binds both PACAP27 and PACAP38 bioactive peptides (PubMed:32047270, PubMed:35477937, PubMed:36385145). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors. Activates cAMP-dependent pathway (PubMed:32047270, PubMed:33715378, PubMed:35477937, PubMed:36385145). May regulate the release of adrenocorticotropin, luteinizing hormone, growth hormone, prolactin, epinephrine, and catecholamine. May play a role in spermatogenesis and sperm motility. Causes smooth muscle relaxation and secretion in the gastrointestinal tract (PubMed:32047270, PubMed:33715378).

关联

项与 ADCYAP1R1 相关的药物

Anti-CGRPR/PAC1R bispecific antibody(Amgen)

抗CGRPR/PAC1R双抗(Amgen)

靶点

ADCYAP1R1 x CGRP receptor

作用机制

ADCYAP1R1拮抗剂 [+1]

在研机构

Amgen, Inc.

原研机构

Amgen, Inc.

在研适应症

头痛

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

BAY 2686013

靶点

ADCYAP1R1

作用机制

ADCYAP1R1拮抗剂

在研机构

Bayer AG

原研机构

Bayer AG

在研适应症

疼痛

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

SPAM1

靶点

ADCYAP1R1

作用机制

ADCYAP1R1 modulators

在研机构

暨南大学

原研机构

暨南大学

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 ADCYAP1R1 相关的临床试验

NCT03238781

/ Completed临床2期

A Phase 2a Randomized Double-blind Placebo Controlled Study to Evaluate the Efficacy and Safety of AMG 301 in Migraine Prevention

To evaluate the effect of AMG 301 compared to placebo on the change from the baseline period in monthly migraine days in subjects with migraine.

开始日期2017-09-06

申办/合作机构

Amgen, Inc.

100 项与 ADCYAP1R1 相关的临床结果

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100 项与 ADCYAP1R1 相关的转化医学

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0 项与 ADCYAP1R1 相关的专利（医药）

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367

项与 ADCYAP1R1 相关的文献（医药）

2024-11-01·Neurochemistry International

The pivotal role of PACAP/PAC1R signaling from the anterior insular cortex to the locus coeruleus on anxiety-related behaviors of mice

Article

作者: Miyata, Atsuro ; Nguyen, Thi Thu ; Kambe, Yuki ; Nguyen, Thu Thi ; Waschek, James A. ; Waschek, James A ; Hashiguchi, Kohei

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific receptor (PAC1R) are widely present in the central nervous system (CNS), and PACAP/PAC1R signaling has been implicated in anxiety-related behaviors. The locus coeruleus (LC), with its extensive noradrenergic (NA) projections throughout the CNS, is also implicated in anxiety. Although the LC exhibits a high expression of PAC1R, the precise role of PACAP/PAC1R signaling in the LC's involvement in anxiety remains unclear. Histochemical analysis confirmed high levels of PAC1R mRNA in the LC and showed that PAC1R gene transcripts were highly localized to NA neurons. Targeted deletion of PAC1R from these cells led to a hyperactive/low anxiety phenotype in the open field and elevated-plus maze tests. Retrograde neurocircuit tracing indicated PACAP neurons from the anterior insular cortex (aIC) and a few other regions projected axons to the LC. The selective activation of PACAP neurons in the aIC led to significantly increased anxiety behavior without a change in overall locomotor activity. Moreover, shRNA PACAP knockdown in the aIC in wild-type mice led to a selective decrease in anxiety. The present results identify an aIC to LC neurocircuit controlling anxiety that critically requires PACAP/PAC1R signaling.

2024-01-01·European Neuropsychopharmacology

Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons

Article

作者: Palkovits, Miklos ; Hedlund, Eva ; Prud'homme, Josee ; Hökfelt, Tomas ; Mechawar, Naguib ; Solarz, Anna ; Turecki, Gustavo ; Mei, Irene ; Nagy, Corina ; Uhlén, Mathias ; Zhong, Wen ; Mulder, Jan ; Aguila, Julio ; Barde, Swapnali

Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.

2024-01-01·Journal of Neuroendocrinology

Dynamic, sex‐ and diet‐specific pleiotropism in the PAC1 receptor‐mediated regulation of arcuate proopiomelanocortin and Neuropeptide Y/Agouti related peptide neuronal excitability by anorexigenic ventromedial nucleus PACAP neurons

Article

作者: Varma, Nandini ; Wagner, Edward J ; Mata-Pacheco, Veronica ; Sayers, Sarah ; Le, Nikki ; Xu, Jenny ; Hernandez, Jennifer

AbstractThis study furthers the investigation of how pituitary adenylate cyclase activating polypeptide (PACAP) and the PAC1 receptor (PAC1R) regulate the homeostatic energy balance circuitry. We hypothesized that apoptotic ablation of PACAP neurones in the hypothalamic ventromedial nucleus (VMN) would affect both energy intake and energy expenditure. We also hypothesized that selective PAC1R knockdown would impair the PACAP‐induced excitation in anorexigenic proopiomelanocortin (POMC) neurones and inhibition of orexigenic neuropeptide Y (NPY)/agouti‐related peptide (AgRP) neurones in the hypothalamic arcuate nucleus (ARC). The results show CASPASE‐3‐induced ablation of VMN PACAP neurones leads to increased energy intake and meal frequency as well as decreased energy expenditure in lean animals. The effects were more robust in obese males, whereas we saw the opposite effects in obese females. We then utilized visualized whole‐cell patch clamp recordings in hypothalamic slices. PAC1R knockdown in POMC neurones diminishes the PACAP‐induced depolarization, increase in firing, decreases in energy intake and meal size, as well as increases in CO2 production and O2 consumption. Similarly, the lack of expression of the PAC1R in NPY/AgRP neurones greatly attenuates the PACAP‐induced hyperpolarization, suppression of firing, decreases in energy intake and meal frequency, as well as increases in energy expenditure. The PACAP response in NPY/AgRP neurones switched from predominantly inhibitory to excitatory in fasted animals. Finally, the anorexigenic effect of PACAP was potentiated when oestradiol was injected into the ARC in ovariectomized females. This study demonstrates the critical role of anorexigenic VMN PACAP neurones and the PAC1R in exciting POMC and inhibiting NPY/AgRP neurons to control homeostatic feeding.

项与 ADCYAP1R1 相关的新闻（医药）

2024-09-04

·drugs

Monoclonal Antibody Tops Placebo for Reducing Migraine Frequency

WEDNESDAY, Sept. 4, 2024 -- The humanized monoclonal antibody directed against the pituitary adenylate cyclase-activating polypeptide (PACAP) ligand, Lu AG09222, is better than placebo for reducing migraine frequency over four weeks, according to a study published in the Sept. 5 issue of the New England Journal of Medicine . Messoud Ashina, M.D., from Copenhagen University Hospital in Denmark, and colleagues conducted a phase 2, double-blind trial involving adults with migraine for whom two to four previous preventive treatments had failed to provide a benefit. The trial included a four-week treatment period and eight-week follow-up period. Participants were randomly assigned to receive a single-dose baseline infusion of 750 mg of Lu AG09222, 100 mg of Lu AG09222, or placebo (97, 46, and 94 individuals, respectively). The researchers found that in the overall population, the mean number of migraine days per month was 16.7, and the mean change from baseline over weeks 1 through 4 was −6.2 and −4.2 days in the Lu AG09222 750-mg group and placebo group, respectively (difference, −2.0 days). During the 12-week observation period, adverse events with a higher incidence in the Lu AG09222 750-mg group versus the placebo group included COVID-19 (7 versus 3 percent), nasopharyngitis (7 versus 4 percent), and fatigue (5 versus 1 percent). "This finding establishes proof of concept, supporting the notion that inhibition of PACAP signaling by Lu AG09222 represents a potentially effective mechanism for migraine prevention," the authors write. The study was partially funded by H. Lundbeck, which is developing Lu AG09222.

临床2期临床结果