Disease relevance of Adcy1

• Thus, AC1 and AC8 are critical modulators of neurodegeneration induced by activity blockade in the neonatal brain and represent genetic loci that may potentially modify the severity of fetal alcohol syndrome [1].
• Our findings provide direct evidence that AC1 plays an important role in neuronal excitotoxicity and may serve as a therapeutic target for preventing excitotoxicity in stroke and neurodegenerative diseases [2].
• The ganglion cell layer and the inner nuclear layer (INL) were immunoreactive for both Ca(2+)-sensitive (AC1, AC3) and Ca(2+)-insensitive (AC2, AC4) isoforms of adenylyl cyclase [3].
• A nucleotide regulatory site for somatostatin inhibition of adenylate cyclase in S49 lymphoma cells [4].
• In the course of examining stimulation of the B16 murine melanoma adenylate cyclase by melanocyte-stimulating hormone (MSH) and by the diterpene forskolin, we noted that tumour cell clones isolated from common parent cell populations differed widely in their responses to these agonists [5].

Psychiatry related information on Adcy1

• To gain some insight into regulatory systems that might be operative during early human development, we have characterized the alterations that occur in the hormonal responsiveness of human embryonal carcinoma cell adenylate cyclase with differentiation in response to 10 microM retinoic acid [6].
• Their opposing roles in regulating neuronal activities, such as locomotion and alcohol consumption, are mediated by their opposite actions on adenylate cyclase, which often serves as "co-incidence detector" of various activators [7].
• Forskolin, an activator of adenylate cyclase, depressed spontaneous locomotor activity when injected intracerebroventricularly into mice in doses of 10 and 100 micrograms [8].
• Further evaluation of these compounds disclosed that, like neuroleptics, they blocked dopamine-stimulated adenylate cyclase, displaced 3H-spiperone in vitro, altered dopamine synthesis, and decreased conditioned avoidance and intracranial self-stimulation behavior [9].

High impact information on Adcy1

• We identified adenylyl cyclase type I (Adcy1) as the gene disrupted in brl mutant mice by fine mapping of proximal chromosome 11, enzyme assay, mutation analysis and examination of mice homozygous for a targeted disruption of Adcy1 [10].
• Crhr1 is highly expressed in the anterior pituitary, neocortex, hippocampus, amygdala and cerebellum, and activation of this receptor stimulates adenylate cyclase [11].
• Increased expression of the c-fos proto-oncogene, presumably a consequence of increased adenylate cyclase activity, may be important in the pathogenesis of the bone lesions in patients with fibrous dysplasia [12].
• Development of activatable adenylate cyclase in the preimplantation mouse embryo and a role for cyclic AMP in blastocoel formation [13].
• Development of activatable adenylate cyclase requires transcription but is independent of the fifth nuclear replication, cell division, and compaction [13].

Chemical compound and disease context of Adcy1

• The cyc- variants of S49 lymphoma cells have served as powerful tools for studying the components and mechanisms of hormone-induced adenylate cyclase stimulation, as these cells are deficient in the guanine nucleotide regulatory site (Ns) mediating hormone, guanine nucleotide, cholera toxin and fluoride-induced stimulations of the enzyme [4].
• Isoproterenol, a stimulator of adenylate cyclase, was used to select a stable variant clone of mouse lymphosarcoma cells deficient in the enzyme [14].
• High propensity for breast cancer in mice was associated with low dopamine-stimulated adenylate cyclase activity in the brain, low spontaneous motorization, and low motor responses to injections of the catecholamine precursor, L-dopa [15].
• The adenylate cyclase toxin of Bordetella pertussis binds to target cells via the alpha(M)beta(2) integrin (CD11b/CD18) [16].
• Thus Ewing's sarcomas are relatively rich in beta-adrenergic sites, and several tumors appear to have a coupling lesion involving guanine nucleotide-dependent regulatory protein interaction with beta-adrenergic receptors and adenylate cyclase, similar in phenotype to that described in the (unc) variant of S49 mouse lymphoma [17].

Biological context of Adcy1

• We have recently identified the causative mutation of the barrelless (Adcy1brl) phenotype as an integration of a 5.7-kb ETn in an intron of the adenylyl cyclase type I (Adcy1) gene [18].
• In all these structures, the peak of AC1 gene expression occurs during early postnatal life, decreasing by P10 [19].
• We identify RIMs as important phosphorylation targets for AC1 in the presynaptic terminal [20].
• Mossy fiber/CA3 long-term potentiation (LTP) is hypothesized to depend on cAMP signals generated by Ca2+-stimulated adenylyl cyclases AC1 or AC8 [21].
• These results demonstrate how efficient synaptic transmission mediated by AC1 function contributes to the development of cortical barrel maps [20].

Anatomical context of Adcy1

• Ipsilateral retinal axons remained exuberant in the AC1(-/-) mice, with overlapping retinal projections from both eyes in the superior colliculus and the visual thalamus [22].
• Thus, only AC1 is required for the maturation of the retinal axon terminals whereas AC5 and AC8 are not needed [22].
• AC1 is expressed in retinal ganglion cells (RGCs) from embryonic day 15 to adulthood with a peak during the first postnatal week [23].
• AC1 and AC8 in the anterior cingulate cortex (ACC) and the spinal cord were previously shown to be important in subcutaneous inflammatory pain [24].
• Transient expression of AC1 is found in the striatum, the dorsal thalamus, the trigeminal nerve nuclei, the Purkinje cells of the cerebellum, the interneurons of the hippocampus, and the retinal ganglion cells [19].

Associations of Adcy1 with chemical compounds

• Adenylate cyclase inhibitor (SQ 22536), phospholipase C inhibitors (neomycin or U 73122), and protein kinase C (PKC) inhibitors (bisindolylmaleimide I or staurosporine) inhibited the ATP-induced increase in [(3)H]thymidine incorporation [25].
• Here we show that wild-type, AC1, AC8, or AC1&8 double knockout (DKO) mice were indistinguishable in tests of acute pain, whereas behavioral responses to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant, were reduced or abolished in AC1&8 DKO mice [26].
• Spatiotemporal localization of the calcium-stimulated adenylate cyclases, AC1 and AC8, during mouse brain development [19].
• Here, we report that genetic deletion of AC1 significantly attenuated neuronal death induced by glutamate in primary cultures of cortical neurons, whereas AC8 deletion did not produce a significant effect [2].
• To explore the possible roles of AC1 in cell death in vivo, we studied neuronal excitotoxicity induced by an intracortical injection of NMDA [2].

Physical interactions of Adcy1

• This phenomenon is correlated with the appearance of functional adenylate cyclase coupled PTH/PTHrP-receptors [27].
• We demonstrate that this effect is dependent on the internalization of somatostatin-receptor complexes and that it is totally independent from the peptide-induced inhibition of adenylate cyclase [28].
• The pharmacological characterization of the 5-HT receptor negatively coupled to adenylate cyclase in mouse embryonic cortical neurons indicates that it differs from the 5-HT1A receptor found in hippocampal neurons [29].
• The presence of vasoactive intestinal polypeptide (VIP) receptors coupled to an adenylate cyclase was demonstrated on membranes of neurons or glial cells grown in primary cultures originating from the cerebral cortex, striatum, and mesencephalon of mouse embryos [30].
• Transgenic mice express the mutant form of the alpha subunit of the adenylate cyclase-coupled G alpha s with mutations at codon 201 (R201H) [31].

Enzymatic interactions of Adcy1

• These results strongly suggest that beta AR kinase is able to phosphorylate and desensitize both stimulatory and inhibitory adenylate cyclase-coupled receptors, thus emerging as a general kinase that regulates the function of different receptors in an agonist-specific fashion [32].
• Mechanism of inhibition of adenylate cyclase by phospholipase C-catalyzed hydrolysis of phosphatidylcholine. Involvement of a pertussis toxin-sensitive G protein and protein kinase C [33].

Regulatory relationships of Adcy1

• AC1 and AC8 are expressed widely throughout the brain of neonatal mice, and genetic deletion of both AC1 and AC8 in double-knock-out (DKO) mice enhances ethanol-induced neurodegeneration in the brains of neonatal mice [1].
• In isolated membranes, CRF (100 nM) stimulated adenylate cyclase activity 4- to 5-fold [34].
• Addition of pituitary adenylate cyclase-activating polypeptide-38 to the medium also induced transient Per1 gene expression [35].
• Pituitary adenylate cyclase-activating polypeptide (PACAP) isolated from ovine hypothalamic tissue is a novel neuropeptide which stimulates adenylate cyclase in rat anterior pituitary cell cultures [36].
• IL-2-induced proliferation was inhibited by membrane-permeable dibutyryl cyclic adenosine monophosphate (cAMP) or by the adenylate cyclase activator forskolin [37].

Other interactions of Adcy1

• Therefore, we conducted the present work to test the role of AC1 and AC8 in both acute persistent and chronic muscle pain [24].
• It is hypothesized that Ca2+ stimulation of calmodulin (CaM)-activated adenylyl cyclases (AC1 or AC8) generates cAMP signals critical for late phase LTP (L-LTP) and long-term memory (LTM) [38].
• Capacitative Ca(2+) entry stimulates cAMP synthesis in mouse parotid acini, suggesting that one of the Ca(2+)-sensitive adenylyl cyclases (AC1 or AC8) may play an important role in the regulation of parotid function (Watson, E. L., Wu, Z., Jacobson, K. L., Storm, D. R., Singh, J. C., and Ott, S. M. (1998) Am. J. Physiol. 274, C557-C565) [39].
• Video microscopic analyses show that AC1(brl/brl) axons have modified responses to ephrin-A5: the collapse of the growth cones occurs, but the rearward movement of the axon is arrested [40].
• Moreover, this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice [41].

Analytical, diagnostic and therapeutic context of Adcy1

• In the present study, Northern blot analysis shows that the ETn insertion results in loss of the normal Adcy1 transcript, a finding consistent with the loss-of-function Adcy1brl mutation, and generation of shorter transcripts [18].
• To determine the potential role of other AC isoforms we localized the Adcy genes in the visual centres during development, using in situ hybridization [22].
• Electroretinography (ERG) of adult Adcy1(brl) mutant mice, which are deficient in adenylyl cyclase type 1 (AC1) activity, revealed decreased amplitude of the oscillatory potentials (OP) and of the primary rising phase of the b-wave intensity-response function in scotopic conditions [42].
• The effects of AC1 loss of function in the retina are mimicked by the blockade of ephrin-A5 signaling in WT cocultures [40].
• Mice lacking either AC1 or AC8 genes or DKO did not differ from wild-type mice in short-term antinociceptive responses to morphine measured in the tail-flick analgesia assay [43].

References