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At least 19 recordsLinked to original sources
PubMed1997

Characterization and crystallization of a minimal catalytic core domain from mammalian type II adenylyl cyclase.

Adenylyl cyclases play a pivotal role in signal transduction by carrying out the regulated synthesis of cyclic AMP. The nine cloned mammalian adenylyl cyclases all share two conserved regions of sequence, C1 and C2, which are homologous to each other and are together responsible for catalytic activity. Recombinant C1 and C2 domains catalyze the synthesis of cyclic AMP when they are mixed and activated by forskolin, and C2 domains alone also manifest reduced levels of forskolin-stimulated enzyme activity. Using limited proteolysis and mass spectrometry, we have mapped the boundaries of a minimal stable and active C2 catalytic domain to residues 871-1090 of type II adenylyl cyclase. We report the properties and crystallization of this trimmed domain, termed IIC2-delta 4. Crystals belong to space group P4n2(1)2, where n = 1 or 3; a = b = 81.3, and c = 180.5 A; and there are two molecules per asymmetric unit related by an approximate body centering operation. Flash-frozen crystals diffract anisotropically to 2.2 A along the c* direction and to 2.8 A along the a* and b* directions using synchrotron radiation.

Adenylyl Cyclases↗
PubMed1996

Interaction of the two cytosolic domains of mammalian adenylyl cyclase.

Adenylyl cyclase activity can be reconstituted by simple mixture of the two cytosolic domains of the enzyme after their independent synthesis in Escherichia coli. We have synthesized and purified the C1a domain of type I adenylyl cyclase and the C2 domain of the type II enzyme to assess their interactions with each other and with the activators Gsalpha and forskolin. In the absence of an activator, the fragments associate with low affinity and display low catalytic activity. This basal activity can be stimulated more than 100-fold by either forskolin or activated Gsalpha. Further, the addition of these activators increases the apparent affinity of the fragments for each other. Stimulation of catalysis by Gsalpha and forskolin is synergistic. These data suggest a model wherein either Gsalpha or forskolin enhances association of the other activator with adenylyl cyclase, as well as facilitating the interaction between the C1 and C2 domains of the enzyme.

Adenylyl Cyclases↗
PubMed2004

A soluble C1b protein and its regulation of soluble type 7 adenylyl cyclase.

Adenylyl cyclase (AC) is a prototypical cell-signaling molecule expressed in virtually all organisms from bacteria to man. While C1b, a poorly conserved region within mammalian AC, has been implicated in numerous isoform-specific regulatory properties, no one has purified the C1b region as a functional protein to homogeneity in order to study its role in enzyme function. We hypothesize that C1b is an internal regulatory subunit. To pursue this hypothesis, we constructed several soluble C1b proteins from type VII AC, arriving at one, 7C1b-S, which can be expressed and purified from Escherichia coli. 7C1b-S is relatively stable, as demonstrated by limited proteolytic analysis, circular dichroism, and UV Raman spectroscopy. Using size-exclusion chromatography and co-immunoprecipitation we demonstrate that 7C1b-S interacts with a cardinal activator of AC (Gsalpha) and with the conserved first catalytic domain (C1a) of type VII AC. We show that 7C1b-S inhibits Gsalpha-stimulated and Gsalpha-forskolin stimulated activity in our soluble ACVII model system. On the basis of these results, we suggest that 7C1b-S meets basic criteria to serve as a model protein for the C1b region and may be used as a prototype to develop other isoform C1b soluble model proteins to further investigate the role of this domain in isoform-specific regulation of adenylyl cyclase.

Adenylyl Cyclase Inhibitors↗
PubMed2002

Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases.

Adenylyl cyclase types 1 (AC1) and 8 (AC8), the two major calmodulin-stimulated adenylyl cyclases in the brain, couple NMDA receptor activation to cAMP signaling pathways. Cyclic AMP signaling pathways are important for many brain functions, such as learning and memory, drug addiction, and development. 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. AC1 and AC8 are highly expressed in the anterior cingulate cortex (ACC), and contribute to inflammation-induced activation of CREB. Intra-ACC administration of forskolin rescued behavioral allodynia defective in the AC1&8 DKO mice. Our studies suggest that AC1 and AC8 in the ACC selectively contribute to behavioral allodynia.

Adenylyl Cyclases↗
PubMed1990

Differential expression of low molecular weight form of Gs-alpha in neostriatum and cerebellum: correlation with expression of calmodulin-independent adenylyl cyclase.

Adenylyl cyclase of neostriatal plasma membranes is far less responsive to stimulation by Ca2+/calmodulin than is the enzyme from cerebellum. When these tissues were investigated with antibodies against known G-proteins, no difference could be detected in any G-protein species, other than Gs. Whereas the cerebellum expressed predominantly the large form of Gs-alpha, the neostriatum expressed mainly lower molecular weight forms. The possibility is considered that there is selective association between lower molecular weight forms of Gs and calmodulin-independent forms of adenylyl cyclase.

Adenylyl Cyclases↗
PubMed2001

Persistent interactions between the two transmembrane clusters dictate the targeting and functional assembly of adenylyl cyclase.

Adenylyl cyclases possess complex structures like those of the ATP binding cassette (ABC) transporter family, which includes the cystic fibrosis transmembrane regulator, the P-glycoprotein, and ATP-sensitive K(+) channels [1-4]. These structures comprise a cytosolic N terminus followed by two tandem six-transmembrane cassettes, each associated with a highly homologous (ATP binding) cytosolic loop [5-8]. The catalytic domains, which are located in the two large cytoplasmic loops, are highly conserved and well studied. The crystal structure of these domains has even been described recently [9, 10]. However, nothing is known of the function or organization of the 12 transmembrane segments. In the present study we adopted a range of strategies including live-cell fluorescence resonance energy transfer (FRET) microscopy, coimmunoprecipitation, and functional assays of various truncated and substituted, fluorescently-tagged molecules to analyze the trafficking and activity of this molecule. When expressed as individual peptides, the two transmembrane domains - largely independently of any cytosolic region - formed a tight complex that was delivered to the plasma membrane. This cooperation between the two intact transmembrane domains was essential and sufficient to target the enzyme to the plasma membrane of the cell. The extracellular loop between the ninth and tenth transmembrane segments, which contains an N-glycosylation site, was also necessary. Furthermore, the interaction between the two transmembrane clusters played a critical role in bringing together the cytosolic catalytic domains to express functional adenylyl cyclase activity in the intact cell.

Adenylyl Cyclases↗
PubMed1999

Two-metal-Ion catalysis in adenylyl cyclase.

Adenylyl cyclase (AC) converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate, a ubiquitous second messenger that regulates many cellular functions. Recent structural studies have revealed much about the structure and function of mammalian AC but have not fully defined its active site or catalytic mechanism. Four crystal structures were determined of the catalytic domains of AC in complex with two different ATP analogs and various divalent metal ions. These structures provide a model for the enzyme-substrate complex and conclusively demonstrate that two metal ions bind in the active site. The similarity of the active site of AC to those of DNA polymerases suggests that the enzymes catalyze phosphoryl transfer by the same two-metal-ion mechanism and likely have evolved from a common ancestor.

Adenosine Triphosphate↗
PubMed1999

A functional chimera of mammalian guanylyl and adenylyl cyclases.

Adenylyl and guanylyl cyclases synthesize second messenger molecules by intramolecular esterification of purine nucleotides, i.e., cAMP from ATP and cGMP from GTP, respectively. Despite their sequence homology, both families of mammalian cyclases show remarkably different regulatory patterns. In an attempt to define the functional domains in adenylyl cyclase responsible for their isotypic-common activation by Galphas or forskolin, dimeric chimeras were constructed from soluble guanylyl cyclase alpha1 subunit and the C-terminal halves of adenylyl cyclases type I, II, or V. The cyclase-hybrid generated cAMP and was inhibited by P-site ligands. The data establish structural equivalence and the ability of functional complement at the catalytic sites in both cyclases. Detailed enzymatic characterization of the chimeric cyclase revealed a crucial role of the N-terminal adenylyl cyclase half for stimulatory actions, and a major importance of the C-terminal part for nucleotide specificity.

Adenylyl Cyclase Inhibitors↗
PubMed2005

Gbetagamma activation site in adenylyl cyclase type II. Adenylyl cyclase type III is inhibited by Gbetagamma.

The Gbetagamma complex of heterotrimeric G proteins is the most outstanding example for the divergent regulation of mammalian adenylyl cyclases. The heterodimeric Gbetagamma complex inhibits some isoforms, e.g. ACI, and stimulates the isoforms ACII, -IV, and -VII. Although former studies identified the QEHA region located in the C2 domain of ACII as an important interaction site for Gbetagamma, the determinant of the stimulatory effect of Gbetagamma has not been detected. Here, we identified the C1b domain as the stimulatory region using full-length adenylyl cyclase. The relevant Gbetagamma signal transfer motif in IIC1b was determined as MTRYLESWGAAKPFAHL (amino acids 493-509). Amino acids of this PFAHL motif were absolutely necessary for ACII to be stimulated by Gbetagamma, whereas they were dispensable for Galpha(s) or forskolin stimulation. The PFAHL motif is present in all three adenylyl cyclase isoforms that are activated by Gbetagamma but is absent in other adenylyl cyclase isoforms as well as other known effectors of Gbetagamma. The emerging concept of two contact sites on different molecule halves for effective regulation of adenylyl cyclase is discussed.

Adenylyl Cyclases↗
PubMed1999

Decreased type VI adenylyl cyclase mRNA concentration and Mg(2+)-dependent adenylyl cyclase activities and unchanged type V adenylyl cyclase mRNA concentration and Mn(2+)-dependent adenylyl cyclase activities in the left ventricle of rats with myocardial infarction and longstanding heart failure.

OBJECTIVE: To address the effect of longstanding left ventricular (LV) hypertrophy and failure on LV adenylyl cyclase (AC) gene expression, mRNA concentrations of the main cardiac AC isoforms were measured in the non-infarcted area of LV from rats with myocardial infarction (MI), without (H) or with (F) LV failure, and in control (C) rats. Basal, GTP- and forskolin-stimulated Mg(2+)- and Mn(2+)-dependent AC activities were also measured in F and C rats. METHODS: Two- and six months after MI, steady-state AC mRNA concentrations were assessed by Northern blot analysis and RNase protection assay with isoform-specific cDNA and cRNA probes, respectively. AC activities were assessed on LV microsomal fractions using standard procedures. RESULTS: Types V and VI, and types IV and VII were the major and minor AC mRNA isoforms in both the LVs of F and C rats. Two months after MI, no difference in LV type V or VI mRNA to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratios was observed in rats with H or F compared to C. Six months after MI, no difference in LV type V mRNA concentration was observed between the three rat groups, whether this level was normalized to GAPDH, poly-(A+) or 18S RNAs. In contrast, a 35% decrease in the type VI mRNA to poly-(A+) RNA ratio and a 29% decrease in the type VI mRNA to 18S RNA ratio was observed only in rats with F compared to C (p < 0.05 vs. C for the two comparisons). Two- and six months after MI, basal and forskolin-stimulated Mg(2+)-dependent AC activities were decreased by 30-35% in F rats compared to C (p < 0.05), whereas Mn(2+)-dependent activities were unchanged. CONCLUSION: Longstanding LV hypertrophy and failure resulting from MI in rats is not associated with altered expression of the most abundant, type V, AC mRNA isoform, whereas that of type VI is decreased. The lack of change in Mn(2+)-dependent AC activities in the LV of F rats suggests that this decrease has no functional consequence on overall AC activity and that decreased Mg(2+)-dependent activities are related to alterations occurring upstream.

Adenylyl Cyclases↗
PubMed2005

Effects of forskolin on Kupffer cell production of interleukin-10 and tumor necrosis factor alpha differ from those of endogenous adenylyl cyclase activators: possible role for adenylyl cyclase 9.

Proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) that are released from Kupffer cells may trigger liver inflammation and damage. Hence, endogenous mechanisms for limiting TNF-alpha expression are crucial for avoiding the development of sepsis. Such mechanisms include the anti-inflammatory actions of interleukin-10 (IL-10) as well as signaling induced by the intracellular second messenger cyclic AMP (cAMP). Kupffer cells express several receptors that activate cAMP synthesis, including E-prostanoid receptors and beta-adrenergic receptors. The expression and role of specific adenylyl cyclases in the inhibition of Kupffer cell activation have so far not been subject to study. Pretreatment of rat Kupffer cell cultures with cAMP analogues [8-(4-chlorophenyl)-thio-cAMP], adenylyl cyclase activator (forskolin), or ligands for G-coupled receptors (isoproterenol or prostaglandin E2) 30 min before the addition of lipopolysaccharide (LPS) (1 microg/ml) caused attenuated TNF-alpha levels in culture medium (forskolin/isoproterenol, P < or = 0.05; prostaglandin E2, P < or = 0.01). Forskolin also reduced IL-10 mRNA and protein (P < or = 0.05), which was not observed with the other cAMP-inducing agents. Furthermore, we found that rat Kupffer cells express high levels of the forskolin-insensitive adenylyl cyclase 9 compared to whole liver and that this expression is down-regulated by LPS (P < or = 0.05). We conclude that regulation of TNF-alpha and IL-10 in Kupffer cells depends on the mechanism by which cAMP is elevated. Forskolin and prostaglandin E2 differ in their effects, which suggests a possible role of forskolin-insensitive adenylyl cyclases like adenylyl cyclase 9.

Adenylyl Cyclases↗
PubMedDate not supplied

Modulation of adenylyl cyclase activity in young and adult rat brain cortex. Identification of suramin as a direct inhibitor of adenylyl cyclase.

Adenylyl cyclase (AC) in brain cortex from young (12-day-old) rats exhibits markedly higher activity than in adult (90-day-old) animals. In order to find some possibly different regulatory features of AC in these two age groups, here we modulated AC activity by dithiothreitol (DTT), Fe(2+), ascorbic acid and suramin. We did not detect any substantial difference between the effects of all these tested agents on AC activity in cerebrocortical membranes from young and adult rats, and the enzyme activity was always about two-fold higher in the former preparations. Nevertheless, several interesting findings have come out of these investigations. Whereas forskolin- and Mn(2+)-stimulated AC activity was significantly enhanced by the addition of DTT, increased concentrations of Fe(2+) ions or ascorbic acid substantially suppressed the enzyme activity. Lipid peroxidation induced by suitable combinations of DTT/Fe(2+) or by ascorbic acid did not influence AC activity. We have also observed that PKC- or protein tyrosine kinase-mediated phosphorylation apparently does not play any significant role in different activity of AC determined in cerebrocortical preparations from young and adult rats. Our experiments analysing the presumed modulatory role of suramin revealed that this pharmacologically important drug may act as a direct inhibitor of AC. The enzyme activity was diminished to the same extent by suramin in membranes from both tested age groups. Our present data show that AC is regulated similarly in brain cortex from both young and adult rats, but its overall activity is much lower in adulthood.

Adenylyl Cyclase Inhibitors↗
PubMed1985

The membrane-bound spermatozoal adenylyl cyclase system does not share coupling characteristics with somatic cell adenylyl cyclases.

Membrane-bound adenylyl cyclases from ram, dog, and human sperm are unresponsive to fluoride and guanylylimidodiphosphate [GMP-P(NH)P], two agents that stimulate the adenylyl cyclases of somatic cells by an action on the stimulatory guanine nucleotide-binding regulatory (Ns) component of adenylyl cyclase. We have investigated whether this is because the sperm cell catalytic unit is functionally uncoupled from Ns but, nevertheless, capable of interacting with it, or because the sperm cell adenylyl cyclase system is unique and regulated differently from that of somatic cells. Sperm cells were found to be deficient in Ns, as evidenced by the inability of detergent extracts from sperm cell membranes and fractions to reconstitute Ns-mediated regulation of the adenylyl cyclase of cyc- S49 cells. In addition, attempts to label Ns in sperm cell membranes by [32P]ADP ribosylation with cholera toxin revealed that, if present, Ns is less than 1% of that found in human erythrocyte membranes. This, however, was not the only reason for the unresponsiveness of sperm cell adenylyl cyclase, since fluoride stimulation of the sperm cell enzyme could not be induced by reconstituting it with Ns purified from human erythrocytes (hRBC). When intact hRBC membranes were added to sperm cell fractions in the presence of fluoride, the activities that resulted were greater than the sum of the individual activities. This apparent reconstitution of fluoride regulation of sperm cell adenylyl cyclase could be blocked by lima bean trypsin inhibitor and appears to have resulted from proteolytic activation of the hRBC adenylyl cyclase by sperm proteases. Sperm cell membranes also appear to lack a functional inhibitory regulatory protein of the adenylyl cyclase system (Ni), since they did not contain an ADP-ribosylatable substrate for pertussis toxin action. These results suggest that the sperm cell adenylyl cyclase system is unique and different from that of somatic cells. Sperm cells appear to neither contain Ns or Ni nor possess the ability of their adenylyl cyclase system to interact with Ns from an exogenous source.

Adenylyl Cyclases↗
PubMed1997

The conserved asparagine and arginine are essential for catalysis of mammalian adenylyl cyclase.

Mammalian adenylyl cyclases have two homologous cytoplasmic domains (C1 and C2), and both domains are required for the high enzymatic activity. Mutational and genetic analyses of type I and soluble adenylyl cyclases suggest that the C2 domain is catalytically active and the C1 domain is not; the role of the C1 domain is to promote the catalytic activity of the C2 domain. Two amino acid residues, Asn-1025 and Arg-1029 of type II adenylyl cyclase, are conserved among the C2 domains, but not among the C1 domains, of adenylyl cyclases with 12 putative transmembrane helices. Mutations at each amino acid residue alone result in a 30-100-fold reduction in Kcat of adenylyl cyclase. However, the same mutations do not affect the Km for ATP, the half-maximal concentration (EC50) for the C2 domain of type II adenylyl cyclase to associate with the C1 domain of type I adenylyl cyclase and achieve maximal enzyme activity, or the EC50 for forskolin to maximally activate enzyme activity with or without Gsalpha. This indicates that the mutations at these two residues do not cause gross structural alteration. Thus, these two conserved amino acid residues appear to be crucial for catalysis, and their absence from the C1 domains may account for its lack of catalytic activity. Mutations at both amino acid residues together result in a 3,000-fold reduction in Kcat of adenylyl cyclase, suggesting that these two residues have additive effects in catalysis. A second site suppressor of the Asn-1025 to Ser mutant protein has been isolated. This suppressor has 17-fold higher activity than the mutant and has a Pro-1015 to Ser mutation.

Adenylyl Cyclases↗
PubMed2001

Type-specific regulation of adenylyl cyclase. Selective pharmacological stimulation and inhibition of adenylyl cyclase isoforms.

Crystallographic studies have elucidated the binding mechanism of forskolin and P-site inhibitors to adenylyl cyclase. Accordingly, computer-assisted drug design has enabled us to identify isoform-selective regulators of adenylyl cyclase. After examining more than 200 newly synthesized derivatives of forskolin, we found that the modification at the positions of C6 and C7, in general, enhances isoform selectivity. The 6-(3-dimethylaminopropionyl) modification led to an enhanced selectivity for type V, whereas 6-[N-(2-isothiocyanatoethyl) aminocarbonyl] and 6-(4-acrylbutyryl) modification led to an enhanced selectivity for type II. In contrast, 2'-deoxyadenosine 3'-monophosphate, a classical and 3'-phosphate-substituted P-site inhibitor, demonstrated a 27-fold selectivity for inhibiting type V relative to type II, whereas 9-(tetrahydro-2-furyl) adenine, a ribose-substituted P-site ligand, showed a markedly increased, 130-fold selectivity for inhibiting type V. Consequently, on the basis of the pharmacophore analysis of 9-(tetrahydro-2-furyl) adenine and adenylyl cyclase, a novel non-nucleoside inhibitor, 2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone (NKY80), was identified after virtual screening of more than 850,000 compounds. NKY80 demonstrated a 210-fold selectivity for inhibiting type V relative to type II. More importantly, the combination of a type III-selective forskolin derivative and 9-(tetrahydro-2-furyl) adenine or NKY80 demonstrated a further enhanced selectivity for type III stimulation over other isoforms. Our data suggest the feasibility of adenylyl cyclase isoform-targeted regulation of cyclic AMP signaling by pharmacological reagents, either alone or in combination.

Adenylyl Cyclase Inhibitors↗
PubMed1998

Aeromonas hydrophila adenylyl cyclase 2: a new class of adenylyl cyclases with thermophilic properties and sequence similarities to proteins from hyperthermophilic archaebacteria.

Complementation of an Escherichia coli cya mutant with a genomic library from Aeromonas hydrophila allowed isolation of clones containing two different cya genes. Whereas one of these genes (cyaA) coded for an adenylyl cyclase (AC1) belonging to the previously described class I adenylyl cyclases (ACs), the second one (cyaB) coded for a protein (AC2) that did not match any previously characterized protein when compared to protein sequence databases. In particular, it did not align with any of members of the three known classes of ACs. The purified AC2 enzyme exhibited remarkable biochemical characteristics, namely, an optimum activity at a high temperature (65 degrees C) and at an alkalinic pH (9.5). In order to investigate the functions of both cyclases in A. hydrophila, each gene was inactivated in the chromosome and the resulting mutant strains were examined for physiological alterations. It was shown that, in contrast to cyaA, the cyaB gene was not expressed under usual laboratory growth conditions. However, introduction of a plasmid harboring the cyaB gene in a cyaA mutant, as well as in a cyaA cyaB mutant, allowed cyclic AMP production. AC2 is the first member of a new class of previously unrecognized ACs, and to date, no functional counterpart has been demonstrated in other organisms. However, scanning databases revealed a significant similarity between AC2 and the gene product of three hyperthermophilic archaebacteria: Methanobacterium thermoautotrophicum, Archaeglobus fulgidus, and Methanococcus jannaschii. The possibility of a gene transfer between such phylogenetically divergent bacteria is discussed.

Adenylyl Cyclases↗
PubMed1993

Muscarinic receptor-mediated inhibition of GDP-activated adenylyl cyclase suggests a direct interaction of inhibitory guanine nucleotide-binding proteins and adenylyl cyclase.

To differentiate the effects of GDP and GTP on adenylyl cyclase regulation, adenylyl cyclase in canine sarcolemmal membranes was studied under conditions where only 3-12% of added GDP was converted to GTP by membrane-associated nucleoside diphosphate kinase. Adenylyl cyclase was stimulated up to 180% by GDP at 7-fold lower concentrations than required for stimulation by GTP (GDP half-maximal activation, 120 nM; GTP half-maximal activation, 830 nM). Transphosphorylation of GDP to GTP was blocked completely by the addition of 3 mM UDP. However, UDP did not affect GDP-mediated adenylyl cyclase activation, and guanosine 5'-O-(2-thiodiphosphate) had the same effect on adenylyl cyclase activity as did GDP, indicating that GDP-mediated stimulation of adenylyl cyclase was not due to transphosphorylation of GDP to GTP. Carbachol inhibited GDP-stimulated adenylyl cyclase activity even without addition of GTP; however, this inhibition was clearly dependent upon the endogenous formation of GTP. Half-maximal adenylyl cyclase inhibition by carbachol required the addition of either 330 nM GDP or 25 nM GTP. Taking into account a 3-12% conversion of GDP to GTP by membrane-associated nucleoside diphosphate kinase, sufficient GTP was generated from GDP to support receptor-mediated inhibition of adenylyl cyclase. In addition carbachol-mediated adenylyl cyclase inhibition in the presence of GDP, but not GTP, was blocked completely by 3 mM UDP. In conclusion, GDP-activated adenylyl cyclase could be inhibited by carbachol in the presence of GTP concentrations that were 34-fold below the concentrations needed for GTP-mediated activation of stimulatory guanine nucleotide-binding proteins. In addition, at low GTP concentrations carbachol reduced adenylyl cyclase to levels below "basal" activity (activity in the absence of guanine nucleotides). Although indirectly, these results suggest that carbachol-mediated inhibition of adenylyl cyclase may be independent of Gs activity and possibly due to direct interaction of inhibitory guanine nucleotide-binding proteins and adenylyl cyclase.

Adenylyl Cyclase Inhibitors↗
PubMed1995

Developmentally expressed Ca(2+)-sensitive adenylyl cyclase activity is disrupted in the brains of type I adenylyl cyclase mutant mice.

The type I Ca(2+)-sensitive adenylyl cyclase has been implicated in several forms of synaptic plasticity in vertebrates. Mutant mice in which this enzyme was inactivated by targeted mutagenesis show deficient spatial memory and altered long term potentiation (Wu, Z. L., Thomas, S. A., Villacres, E. C., Xia, Z., Simmons, M. L., Chavkin, C., Palmiter, R. D., and Storm, D. R. (1995) Proc. Natl Acad Sci. U. S. A. 92, 220-224). Long term potentiation in the CA1 region of the rat hippocampus develops during the first 2 weeks after birth and reaches maximal expression at postnatal day 15 with a gradual decline at later stages of development. Here we report that Ca(2+)-stimulated adenylyl cyclase activity in rat hippocampus, cerebellum, and cortex increases significantly between postnatal days 1-16. This increase appears to be due to enhanced expression of type I adenylyl cyclase rather than type VIII adenylyl cyclase, the other adenylyl cyclase that is directly stimulated by Ca2+ and calmodulin. Type I adenylyl cyclase mRNA in the hippocampus increased 7-fold during this developmental period. The developmental expression of Ca(2+)-stimulated adenylyl cyclase activity in mouse brain was attenuated in mutant mice lacking type I adenylyl cyclase. Changes in expression of the type I adenylyl cyclase during the period of long term potentiation development are consistent with the hypothesis that this enzyme is important for neuroplasticity and spatial memory in vertebrates.

Adenylyl Cyclases↗