Catalytic Mechanism and Regulation of Mammalian Adenylyl Cyclases

Tang, Wei-Jen; Hurley, James H.

doi:10.1124/mol.54.2.231

Cited by 181 publications

(187 citation statements)

References 73 publications

(123 reference statements)

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“…However, given the sensitivity of brain AC preparations to Ca 2ϩ / calmodulin, the predominant isoform is likely AC1 and/or AC8 (1, 2). Overall, the structure/activity relationships of compounds 2,4,6,12,13,17, and 20 at the brain ACs (Table III) were similar to those at recombinant mammalian ACs 1, 2, 5, and 6 and S49 wt membrane AC (representing ACs 6 and 7). Moreover, the potencies of compounds 2, 4, 6, 12, 13, 17, and 20 at the brain AC preparations were similar to the potencies of compounds at recombinant AC1, supporting the view that AC1 is a major isoform in the brain AC preparation.…”

Section: Potent and Selective Ac Inhibition By Mant-itp␥s Relative Tomentioning

confidence: 79%

“…Unfortunately, however, 3Ј-d-2Ј-MANT-GMPPNP was not available to us. Phe-889 and Ile-940 are highly conserved among mammalian ACs and sGC (2). Thus, a MANT group at the 2Ј-O-ribosyl position should generally increase the affinity of nucleotides for ACs 1-9 and sGC compared with non-modified nucleotides.…”

Section: Two-and Three-dimensional Models Of the Interactions Of Atp␣mentioning

confidence: 99%

“…Furthermore, the systematic inhibitor analysis of holo-ACs and the respective soluble catalytic subunits of ACs will provide important information on the as yet poorly understood role of the transmembrane domains in AC regulation. Finally, we anticipate that the systematic analysis of the many ACs and GCs not considered in this study (1,2) with purine and pyrimidine nucleotides will yield very interesting results, both in terms of understanding the molecular mechanisms of cyclase function and the identification of novel cyclase inhibitors.…”

Section: Enzyme Kinetics Of Cyclases and Inhibition Of Cyclases By Mamentioning

confidence: 99%

“…over, AC isoforms are differentially expressed in tissues (1,2,16). AC1 knockout mice show impaired cerebellar long term potentiation and impaired development of the somatosensory cortex (17,18); AC3 knockout mice exhibit anosmia (19); AC5 knockout mice show reduced sensitivity to development of heart failure (20); and AC8 knockout mice exhibit altered stress-induced anxiety responses (21).…”

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confidence: 99%

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Differential Inhibition of Adenylyl Cyclase Isoforms and Soluble Guanylyl Cyclase by Purine and Pyrimidine Nucleotides

Gille

Lushington

Mou

et al. 2004

Journal of Biological Chemistry

215

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ACs 1 catalyze the conversion of ATP into the second messenger cAMP, PP i being the second product of the cyclase reaction. Mammals express nine membranous ACs (ACs 1-9) (1, 2) and a sAC that is predominantly expressed in testis (3). Bacillus anthracis and Bacillus pertussis produce the AC toxins EF and ACT, respectively, that are activated by Ca 2ϩ /calmodulin and act through excessive cAMP accumulation in host cells (4,5). sGC is structurally related to ACs 1-9 in the catalytic site and is activated by [6][7][8]. sGC catalyzes the formation of the second messenger cGMP from GTP. ACs 1-9 contain a tandem repeat structure with two transmembrane domains and two cytosolic domains (1, 2). The cytosolic domains are referred to as C1 and C2, respectively. Together, C1 and C2 form the catalytic site of AC. C1 and C2 also contain the regulatory sites for the stimulatory G-protein, G␣ s , for the inhibitory G-protein, G␣ i , and for the diterpene, forskolin. Catalytic activity of all AC isoforms depends on the presence of divalent cations (Mg 2ϩ or Mn 2ϩ ). Membranous ACs possess two Me 2ϩ -binding sites (9 -11). When mixed together, purified C1 and C2 form a functional AC that is efficiently activated by forskolin and G␣ s -GTP␥S (12, 13).AC isoforms differ from each other in their regulation (1, 2). ACs 1-9 are all activated by G␣ s , whereas sAC is activated by HCO 3 Ϫ (14). Forskolin activates ACs 1-8 but not AC9 or sAC. G␣ i inhibits ACs 1, 5, and 6. G-protein ␤␥ subunits exhibit stimulatory or inhibitory effects on AC isoforms. Ca 2ϩ /calmodulin stimulates ACs 1, 3, and 8. In addition, Mg 2ϩ and Mn 2ϩ show differential stimulatory effects on AC isoforms (15). More-

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Section: Potent and Selective Ac Inhibition By Mant-itp␥s Relative Tomentioning

confidence: 79%

Section: Two-and Three-dimensional Models Of the Interactions Of Atp␣mentioning

confidence: 99%

Section: Enzyme Kinetics Of Cyclases and Inhibition Of Cyclases By Mamentioning

confidence: 99%

mentioning

confidence: 99%

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Differential Inhibition of Adenylyl Cyclase Isoforms and Soluble Guanylyl Cyclase by Purine and Pyrimidine Nucleotides

Gille

Lushington

Mou

et al. 2004

Journal of Biological Chemistry

215

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“…Of the ten adenylate cyclase isozymes, all membrane-bound AC isoforms (AC1-9) are expressed in the brain. Their regional distribution is isoform dependent (Chern 2000) and their regulation is complex and isozyme specific (Tang and Hurley 1998). Serotonin, adrenergic, dopaminergic, adenosine, vasoactive intestinal peptide, muscarinic, GABA, and opiod receptors, among others, signal through the cAMP cascade (Lauder 1993) via specific heterotrimeric G proteins.…”

Section: Cyclic Amp Cascadementioning

confidence: 99%

The cyclic AMP phenotype of fragile X and autism

Kelley

Bhattacharyya

Lahvis

et al. 2008

Neuroscience & Biobehavioral Reviews

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Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.

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Adenylyl and Guanylyl Cyclase Assays

et al. 2005

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This unit presents two basic protocols to determine adenylyl cyclase and guanylyl cyclase activity in tissue and cell homogenates, permeabilized cells, or subcellular fractions. Each method is divided into two parts: the enzyme reaction that causes the formation of the labeled cyclic nucleotide, and the separation of cyclic nucleotide products from unreacted nucleotide triphosphates and metabolites using Dowex 50 resin and aluminum oxide chromatographies. In the case of guanylyl cyclase, alternative separation protocols are also provided. Additionally, protocols are provided that describe preparation of both the columns used in the assays and the tissue or cells to be assayed.

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Catalytic Mechanism and Regulation of Mammalian Adenylyl Cyclases

Cited by 181 publications

References 73 publications

Differential Inhibition of Adenylyl Cyclase Isoforms and Soluble Guanylyl Cyclase by Purine and Pyrimidine Nucleotides

Differential Inhibition of Adenylyl Cyclase Isoforms and Soluble Guanylyl Cyclase by Purine and Pyrimidine Nucleotides

The cyclic AMP phenotype of fragile X and autism

Adenylyl and Guanylyl Cyclase Assays

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