Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. Here, we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. We studied the effects of the associated polymorphism in the PACAP gene on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia.
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PMID:Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia. 1738 18

Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1;11) (q42.1;q14.3) translocation that segregates with major psychiatric disorders in a Scottish family. To investigate how DISC1 confers susceptibility to psychiatric disorders, we previously identified fasciculation and elongation protein zeta-1 and Kendrin as DISC1-interacting molecules in a yeast two-hybrid screen of a human brain complementary DNA library. Here, we have further identified a novel DISC1-interacting protein, termed DISC1-Binding Zinc-finger protein (DBZ), which has a predicted C(2)H(2)-type zinc-finger motif and coiled-coil domains. DBZ was co-immunoprecipitated with DISC1 in lysates of PC12 cells and rat brain tissue. The domain of DISC1 interacting with DBZ was close to the translocation breakpoint in the DISC1 gene. DBZ messenger RNA (mRNA) was expressed in human brains, but not in peripheral tissues. In situ hybridization revealed high expression of DBZ mRNA in the hippocampus, olfactory tubercle, cerebral cortex and striatum in rats. Because this pattern of localization was similar to that of the pituitary adenylate cyclase (PAC(1)) receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), which has recently been implicated in neuropsychological functions, we examined whether DISC1/DBZ interaction was involved in the PACAP signaling pathway. PACAP upregulated DISC1 expression and markedly reduced the association between DISC1 and DBZ in PC12 cells. A DISC1-binding domain of DBZ reduced the neurite length in PC12 cells after PACAP stimulation and in primary cultured hippocampal neurons. The present results provide some new molecular insights into the mechanisms of neuronal development and neuropsychiatric disorders.
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PMID:A novel DISC1-interacting partner DISC1-Binding Zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth. 1738 5

Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1:1) (q42.1;q14.3) translocation that segregates with major psychiatric disorders in a Scottish family. To elucidate how DISC1 confers susceptibility to psychiatric disorders, identification of the molecules, which bind to the domain close to the translocation breakpoint in the DISC1 gene, was performed and fasciculation and elongation protein zeta-1 (Fez1), a novel DISC1-interacting protein, termed DISC1-binding zinc-finger protein (DBZ) and Kendrin were identified. The DISC1-Fez1 interaction is up-regulated by nerve growth factor (NGF) and involved in neurite extension. Transient dissociation of the DISC1-DBZ interaction by pituitary adenylate cyclase-activating polypeptide (PACAP) causes neurite extension. Furthermore, single-nucleotide polymorphisms association studies in a Japanese population have shown the relation of the Fez1, PACAP and PACAP receptor (PAC1) genes to schizophrenia. In schizophrenia with DISC1 translocation carrier, the DISC1-Fez1 and DISC1-DBZ interaction is disrupted, and it is likely that neural circuit formation remains immature, suggesting that schizophrenia is a neurodevelopmental disease. On the other hand, the DISC1-Kendrin interaction is suggested to be involved in microtubule network formation and an association between single-nucleotide polymorphisms of the Kendrin gene and bipolar disease has also been suggested in a Japanese population. This demonstrates that a part of bipolar disease is also a neurodevelopmental disorder.
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PMID:Molecular mechanism of schizophrenia with reference to disrupted-in-schizophrenia 1 (DISC1). 1766 24

This review focuses on two pharmacologic approaches to the functional evaluation of new target molecules for drug discovery. One is the development of a novel specific antagonist of the Na(+)-Ca(++) exchanger (NCX) SEA0400. The other is a comprehensive analysis of the functions of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide ligand for G protein-coupled receptors. NCX is the one of the last target molecules regulating the cellular Ca(++) concentration. There was no efficient way to address the pathophysiologic roles of NCX until a specific antagonist, 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), was developed. Our recent studies using SEA0400 clearly showed the possible roles of NCX in several pathologic states of cardiovascular and nervous tissues. In our second approach including gene-targeting methods, we found new, unexpected roles of PACAP in higher brain functions, such as psychomotor, cognition, photoentrainment, and nociception. Based on these experimental findings, a genetic association study in schizophrenia patients revealed that the single-nucleotide polymorphisms of the PACAP gene are significantly associated with the hypofunction of the hippocampus. Regarding the peripheral roles of PACAP, we found that PACAP is involved not only in the regulation of insulin secretion in pancreatic islets, but also in the regulation of islet turnover. In subsequent phenotypic analysis of PACAP transgenic mice, we identified novel candidate genes that probably have promising functional roles.
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PMID:[Molecular pharmacologic approaches to functional analysis of new biological target molecules for drug discovery]. 1791 22

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1) is a neuropeptide with neurotransmission modulating activity. The associations of the PACAP gene with schizophrenia and hippocampal volume have been reported. We recently reported depression-like behavior in the forced swimming test in PACAP deficient mice. Here we examined a possible association between the PACAP gene and major depressive disorder (MDD) in 637 patients and 967 controls and found that a genetic variant in the gene was associated with MDD. The present results suggest that PACAP signaling might contribute to the pathogenesis of MDD.
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PMID:Possible association between the pituitary adenylate cyclase-activating polypeptide (PACAP) gene and major depressive disorder. 1991 36

Two pituitary adenylate cyclase-activating polypeptide (PACAP)-signaling pathways linked to schizophrenia were reviewed. One pathway regulates the association between disrupted-in-schizophrenia 1 (DISC1) and DISC1-binding zinc-finger protein via PACAP, and the other inhibits stathmin1 expression via PACAP. PACAP reduces the association of the binding between DISC1 (a potential susceptibility gene for major psychiatric disease) and DISC1-binding zinc-finger protein (which binds to DISC1 near the translocation site) to induce neurite outgrowth. In addition, an association between SNPs of the PACAP or PAC1 genes and schizophrenia has been reported. On the other hand, expression of stathmin1, which induces abnormal axonal arborization, is upregulated in PACAP-knock out mice and the brains of patients with schizophrenia. Thus it is likely that, in the schizophrenic brain, the neural development depending on these two systems has been disturbed. The possibility that the regulation of these two systems could lead to new treatments for schizophrenia is also discussed.
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PMID:Role of the PACAP-PAC1-DISC1 and PACAP-PAC1-stathmin1 systems in schizophrenia and bipolar disorder: novel treatment mechanisms? 1995 95

Mice lacking the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) (PACAP(-/-)) display behavioral abnormalities, and genetic variants of the genes encoding PACAP are associated with schizophrenia. Clinical studies show that environmental factors, besides genetic factors, play a key role in etiology of many psychiatric disorders. This study examined the effects of environmental factors such as short-term social isolation and an enriched environment on behavioral abnormalities of PACAP(-/-) mice. Rearing in isolation for 2-weeks from 4-weeks old induced hyperlocomotion and aggressive behaviors in the PACAP(-/-) mice without affecting the behavioral performance of the wild-type controls. Adult PACAP(-/-) mice showed not only hyperactivity, jumping behavior, and depression-like behavior, but also decreased social interaction. These abnormal behaviors were improved by rearing for 4-weeks in an early enriched environment (from 4-weeks old), although the deficits of prepulse inhibition (PPI) were not influenced by the enriched condition. In contrast, rearing for 4-weeks in late enriched environment (from 8-weeks old) did not affect the hyperactivity and jumping behaviors in the PACAP(-/-) mice. These results suggest that abnormal behaviors except PPI deficits in PACAP(-/-) mice depend on the environmental factors during the early stages of development.
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PMID:Environmental factors during early developmental period influence psychobehavioral abnormalities in adult PACAP-deficient mice. 2014 62

The adenylate cyclase-activating polypeptide 1 (ADCYAP1) gene encodes a neuropeptide with neurotransmission activity, which is known as the pituitary adenylate cyclase-activating polypeptide. Associations of two polymorphisms, rs1893154 and rs2856966 (Asp54Gly), in the ADCYAP1 gene with schizophrenia were reported earlier by a Japanese case-control study. In this study, we tried to confirm the association in 2027 Japanese patients with schizophrenia and 2058 controls. The power to detect an association was more than 0.9. However, we did not detect allelic associations of rs1893154 with schizophrenia (P=0.36). Although rs2856966 was nominally significant (P=0.045), the association was in the opposite direction from that reported earlier. Combined data and meta-analysis of the two studies comprising nearly 6000 Japanese case-control patients did not show significant associations (P=0.53-0.86). It is concluded that single-nucleotide polymorphisms, including Asp54Gly, of the ADCYAP1 gene are unlikely to play a sizeable role in the genetic susceptibility to schizophrenia.
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PMID:Replication study of association between ADCYAP1 gene polymorphisms and schizophrenia. 2041 43

In the central nervous system, pituitary adenylate cyclase-activating polypeptide (PACAP) exerts different actions as neurotransmitter, neuromodulator, neurotrophic and neuroprotective factors via multiple signaling pathways. PACAP plays an important protective role in the nervous system diseases, such as focal cerebral ischemia, traumatic brain injury (TBI), schizophrenia, anxiety disorders Parkinson's disease and Alzheimer's disease. Now, we reviewed the research advances about the protective role of PACAP in the nervous system diseases.
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PMID:[Research advance of the protective role of PACAP in the nervous system diseases]. 2206 19

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are members of a superfamily of structurally related peptide hormones that includes glucagon, glucagon-like peptides, secretin, gastric inhibitory peptide (GIP) and growth hormone-releasing hormone (GHRH). VIP and PACAP exert their actions through three GPCRs - PAC(1) , VPAC(1) and VPAC(2) - belonging to class B (also referred to as class II, or secretin receptor-like GPCRs). This family comprises receptors for all peptides structurally related to VIP and PACAP, and also receptors for parathyroid hormone, corticotropin-releasing factor, calcitonin and related peptides. PAC(1) receptors are selective for PACAP, whereas VPAC(1) and VPAC(2) respond to both VIP and PACAP with high affinity. VIP and PACAP play diverse and important roles in the CNS, with functions in the control of circadian rhythms, learning and memory, anxiety and responses to stress and brain injury. Recent genetic studies also implicate the VPAC(2) receptor in susceptibility to schizophrenia and the PAC(1) receptor in post-traumatic stress disorder. In the periphery, VIP and PACAP play important roles in the control of immunity and inflammation, the control of pancreatic insulin secretion, the release of catecholamines from the adrenal medulla and as co-transmitters in autonomic and sensory neurons. This article, written by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) subcommittee on receptors for VIP and PACAP, confirms the existing nomenclature for these receptors and reviews our current understanding of their structure, pharmacology and functions and their likely physiological roles in health and disease. More detailed information has been incorporated into newly revised pages in the IUPHAR database (http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=67).
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PMID:Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. 2228 55


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