Alternative titles; symbols
HGNC Approved Gene Symbol: ADCY8
Cytogenetic location: 8q24.22 Genomic coordinates (GRCh38): 8:130,780,301-131,040,909 (from NCBI)
Adenylyl cyclase (EC 4.6.1.1) catalyzes the transformation of ATP into cyclic AMP. The enzymatic activity is under the control of several hormones, and different polypeptides participate in the transduction of the signal from the receptor to the catalytic moiety. Stimulatory or inhibitory receptors (Rs and Ri) interact with G proteins (Gs and Gi) that exhibit GTPase activity and they modulate the activity of the catalytic subunit of the adenylyl cyclase (Parma et al., 1991).
Parma et al. (1991) cloned a cDNA corresponding to human brain adenylyl cyclase, symbolized by them as HBAC1. Sequencing of the isolated cDNAs revealed 2 polyadenylation signals, but none contained the 5-prime coding region of HBAC. The deduced 675-amino acid C-terminal portion contains 6 putative transmembrane segments followed by a long cytoplasmic tail. The latter domain contains a 250-amino acid region highly similar to bovine and rat adenylate and guanylate cyclases, and nonmammalian adenylate cyclases. Northern blot analysis detected transcripts of 10.5 and 5.2 in human brain.
By screening a human newborn brainstem cDNA library, Defer et al. (1994) obtained full-length ADCY8. The deduced 1,251-amino acid protein has a calculated molecular mass of 140 kD. It has 12 membrane-spanning segments grouped into 2 transmembrane domains, and uniquely long N- and C-terminal tails. It has 2 putative N-glycosylation sites between membrane spanning regions 9 and 10, another N-glycosylation site between membrane spanning regions 11 and 12, and it has a potential protein kinase A (see PRKACA, 601639) phosphorylation site in the first cytoplasmic loop. By screening a testis cDNA library, Defer et al. (1994) identified a partial ADCY8 splice variant with a 90-bp deletion leading to loss of a region between membrane spans 9 and 10, including 2 potential N-glycosylation sites.
By semiquantitative RT-PCR, Ludwig and Seuwen (2002) found weak expression of ADCY8 in brain and testis and no expression in any other tissue examined.
By analyzing rat and bovine Adcy8 isoforms, Gu and Cooper (1999) identified N- and C terminal calmodulin (see CALM1, 114180)-binding sites in mammalian ADCY8.
Defer et al. (1994) found that the region upstream of the ADCY8 start codon was highly GC rich. Ludwig and Seuwen (2002) determined that the ADCY8 gene contains 18 exons and spans 262.3 kb.
Ca(2+) stimulation of ADCY8 occurs through loosely bound calmodulin. By mutation analysis of the N-terminal calmodulin-binding domain of mammalian Adcy8, Gu and Cooper (1999) determined that this domain makes a minor contribution to the Ca(2+) stimulation of Adcy8 activity, although it may be involved in calmodulin trapping. Mutagenesis and functional assays of the C-terminal calmodulin-binding site indicated that this site is largely responsible for the Ca(2+) stimulation of Adcy8. Removal of the C-terminal calmodulin-binding region resulted in a hyperactivated enzyme and loss of Ca(2+) sensitivity.
Simpson et al. (2006) found that the N-terminal calmodulin-binding domain of rodent Adcy8 had a role in recruiting calmodulin and that this recruitment was essential for stimulation by Ca(2+) in vivo.
Among 304 Swiss individuals tested and genotyped, de Quervain and Papassotiropoulos (2006) found a significant association (p = 0.00008) between short-term episodic memory performance and genetic variations in a 7-gene cluster consisting of the ADCY8, PRKACG (176893), CAMK2G (602123), GRIN2A (138253), GRIN2B (138252), GRM3 (601115), and PRKCA (176960) genes, all of which have well-established molecular and biologic functions in animal memory. Functional MRI studies in an independent set of 32 individuals with similar memory performance showed a correlation between activation in memory-related brain regions, including the hippocampus and parahippocampal gyrus, and genetic variability in the 7-gene cluster. De Quervain and Papassotiropoulos (2006) concluded that these 7 genes encode proteins of the memory formation signaling cascade that are important for human memory function.
By in situ hybridization to metaphase chromosomal spreads using the human brain cDNA probe, Stengel et al. (1992) showed that the ADCY8 gene is located on chromosome 8q24.2. A highly homologous gene, ADCY2 (103071), was assigned to 5p15.3 by the same method.
Wei et al. (2002) found that wildtype, Adcy1 (103072)-null, Adcy8-null, and Adcy1-Adcy8 double-knockout mice were indistinguishable in their response to acute pain. However, behavioral responses to inflammatory stimuli were significantly reduced in mice lacking Adcy1 or Adcy8, and more profoundly compromised in Adcy1 and Adcy8 double-knockout mice. Both Adcy1 and Adcy8 were expressed at high levels in 2 pain-related forebrain areas, the anterior cingulate cortex and the insular cortex, and at a low level in the spinal cord. Injection of an adenylate cyclase activator in the anterior cingulate cortex rescued the response to noxious stimuli in Adcy1-Adcy8 double-knockout mice.
Defer, N., Marinx, O., Stengel, D., Danisova, A., Iourgenko, V., Matsuoka, I., Caput, D., Hanoune, J. Molecular cloning of the human type VIII adenylyl cyclase. FEBS Lett. 351: 109-113, 1994. [PubMed: 8076676] [Full Text: https://doi.org/10.1016/0014-5793(94)00836-1]
de Quervain, D. J.-F., Papassotiropoulos, A. Identification of a genetic cluster influencing memory performance and hippocampal activity in humans. Proc. Nat. Acad. Sci. 103: 4270-4274, 2006. [PubMed: 16537520] [Full Text: https://doi.org/10.1073/pnas.0510212103]
Gu, C., Cooper, D. M. F. Calmodulin-binding sites on adenylyl cyclase type VIII. J. Biol. Chem. 274: 8012-8021, 1999. [PubMed: 10075700] [Full Text: https://doi.org/10.1074/jbc.274.12.8012]
Ludwig, M.-G., Seuwen, K. Characterization of the human adenylyl cyclase gene family: cDNA, gene structure, and tissue distribution of the nine isoforms. J. Recept. Signal Transduct. Res. 22: 79-110, 2002. [PubMed: 12503609] [Full Text: https://doi.org/10.1081/rrs-120014589]
Parma, J., Stengel, D., Gannage, M.-H., Poyard, M., Barouki, R., Hanoune, J. Sequence of a human brain adenylyl cyclase partial cDNA: evidence for a consensus cyclase domain. Biochem. Biophys. Res. Commun. 179: 455-462, 1991. [PubMed: 1715695] [Full Text: https://doi.org/10.1016/0006-291x(91)91392-p]
Simpson, R. E., Ciruela, A., Cooper, D. M. F. The role of calmodulin recruitment in Ca(2+) stimulation of adenylyl cyclase type 8. J. Biol. Chem. 281: 17379-17389, 2006. [PubMed: 16613843] [Full Text: https://doi.org/10.1074/jbc.M510992200]
Stengel, D., Parma, J., Gannage, M.-H., Roeckel, N., Mattei, M.-G., Barouki, R., Hanoune, J. Different chromosomal localization of two adenylyl cyclase genes expressed in human brain. Hum. Genet. 90: 126-130, 1992. [PubMed: 1427768] [Full Text: https://doi.org/10.1007/BF00210755]
Wei, F., Qiu, C.-S., Kim, S. J., Muglia, L., Maas, J. W., Jr., Pineda, V. V., Xu, H.-M., Chen, Z.-F., Storm, D. R., Muglia, L. J., Zhuo, M. Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron 36: 713-726, 2002. [PubMed: 12441059] [Full Text: https://doi.org/10.1016/s0896-6273(02)01019-x]