Interactions between Neurotransmitters that Regulate cAMP and Intracellular Ca2+ Levels in the CNS

  • D. M. F. Cooper
  • K. K. Caldwell
  • E. Perez-Reyes
  • M. K. Ahlijanian
  • W. Schlegel
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 236)


Two major second messenger signalling systems play prominent roles in the regulation of neuronal activity — that which modulates intracellular cAMP levels and that which results in an elevation in intracellular Ca2+ concentrations. Intracellular Ca2+ is now known to be mobilized as a consequence of receptor modulation of inositol phosphate metabolism.1 It is widely recognised that both of these pathways can lead to changes in the level of intracellular protein phosphorylation through the mediation of distinct protein kinases -sometimes converging on a single target protein, as is the situation in the case of tyrosine hydroxylase.2 However, less widely recognized is the fact that these signalling systems also interact more immediately at the level of the generation of their rimary signals. Recent studies — for instance those by Jakobs et al3 — indicate that, in some cells, the Ca2+-activated, protein kinase C, eliminates hormone inhibition of adenylate cyclase which is mediated by inhibitory GTP regulatory elements. It has also been recognised for some time that Ca2+/calmodulin regulates a specific cyclic AMP phosphodiesterase in neuronal tissue; this interaction provides a mechanism whereby Ca2+ signals can decrease cAMP levels.4,5 Thus, the potential for interaction between systems that utilize Ca2+ and cAMP has already been established. In order to explore other potential mechanisms by which these two systems interact at the level of signal generation, recent studies from these laboratories have focussed on two major issues: 1) additional functions that may be served by putative “cyclase-inhibitory” receptors in the CNS. The physiological significance of adenylate cyclase inhibition in neuronal tissue has often been questioned, since the magnitude of the effect is so modest -rarely exceeding 25%. In the present studies additional functions supported by “cyclase inhibitory” receptors are investigated; and, 2) the impact of Ca2+-signals on the regulation of adenylate cyclase by cyclase-linked receptors. Over the past few years, a focus in one of these laboratories ha been the fact — first reported by Brostrom et al.6 — that Ca2+/calmodulin can regulate neuronal adenylate cyclase — particularly in terms of its implications for neurotransmitter regulation of adenylate cyclase. Initial studies on the hippocampal system had indicated that adenosine-Al receptor-mediated inhibition of adenylate cyclase could occur only upon Ca2+/calmodulin stimulation of activity.7 Current studies have attempted to determine how widespread this phenomenon is within the nervous system, whether it applies to all inhibitory neurotransmitters8,9 and the implications of this regulation for stimulatory neurotransmission.


Adenylate Cyclase Pertussis Toxin Inositol Phosphate Adenylate Cyclase Activity Adenosine Analogue 


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  1. 1.
    Berridge, M.J., and Irvine, R.F. (1984) Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312, 315–320.CrossRefGoogle Scholar
  2. 2.
    Browning, M.D., Huganir, R. and Greengard, P. (1985) Protein phosphorylation and neuronal function. J. Neurochem. 45, 11–23.CrossRefGoogle Scholar
  3. 3.
    Jakobs, K.H., Bauer, S., and Watanabe, Y. (1985) Modulation of adenylate cyclase of human platelets by phorbol ester. Impairment of the hormone-sensitive inhibitory pathway. Eur. J. Biochem. 151, 425–430.CrossRefGoogle Scholar
  4. 4.
    Cheung, W.Y. (1980) Calmodulin plays a pivotal role in cellular regulation. Science 207, 19–27.CrossRefGoogle Scholar
  5. 5.
    Klee, C.B., Crouch, T.H., and Richman, P.G. (1980) Calmodulin. Ann. Rev. Biochem. 49, 489–515.CrossRefGoogle Scholar
  6. 6.
    Brostrom, C.O., Huang, Y., Breckenridge, B.M., and Wolff, D.J. (1975) Identification of calcium-binding protein as a calciumdependent regultor of brain adenylate cyclase. Proc. Natl. Acad. Sci. USA 72, 64–68.CrossRefGoogle Scholar
  7. 7.
    Girardot, J.-M., Kempf, J., and Cooper, D.M.F. (1983) Role of calmodulin in the effect of guanyl nucleotides on rat hippocampal adenylate cyclase: involvement of adenosine and opiates. J. Neurochem. 41, 848–859.CrossRefGoogle Scholar
  8. 8.
    Perez-Reyes, E., and Cooper, D.M.F. (1987) Calmodulin stimulation of the rat cerebral cortical adenylate cyclase is required for the detection of guanine nucleotide-or hormone-mediated inhibition. Mol. Pharmacol., 32, 212–216.Google Scholar
  9. 9.
    Ahlijanian, M.K. and Cooper, D.M.F (1987) Calmodulin may play a pivotal role in neurotransmitter-mediated inhibition and stimulation of rat cerebellar adenylate cyclase. Mol. Pharmacol., 32, 127–132.Google Scholar
  10. 10.
    Perez-Reyes, E., and Cooper, D.M.F (1986) Interaction of the inhibitory GTP regulatory component with soluble cerebral cortical adenylate cyclase. J. Neurochem. 46, 1508–1516.CrossRefGoogle Scholar
  11. 11.
    Petcoff, D.W., and Cooper, D.M.F. (1987) Adenosine receptor agonists inhibit inositol phosphate accumulation in rat striatal slices. Eur. J. Pharmacol. 137, 269–271.CrossRefGoogle Scholar
  12. 12.
    Schlegel, W., Waurin, F., Zbaren, C., Wolheim, C.B., and Zahnd, G.R. (1985) Pertussis toxin selectively abolishes hormone induced lowering of cytosolic calcium in GH3 cells. FEBS Lett. 189, 27–32.CrossRefGoogle Scholar
  13. 13.
    Dorflinger, L.J., and Schonbrunn, A. (1985) Adenosine inhibits prolactin and growth hormone secretion in a clonal pituitary cell line. Endocrinology, 117, 2330–2338.CrossRefGoogle Scholar
  14. 14.
    Hill, S.J., and Kendall, D.A. (1987) Adenosine inhibits histamine- induced inositol phospholipid hydrolysis in mouse cerebral cortex slices. Br. J. Pharmacol. 90, 77 P.Google Scholar
  15. 15.
    Enjalbert, A., Sladeczek, F., Guillon, G., Bertrand, P., Shu, C., Epelbaum, J., Garcia-Sainz, A., Jard, S., Lombard, C., Kordon, D., and Bockaert, J. (1986) Angiotensin II and dopamine modulate both cAMP and inositol phosphate production in anterior pituitary cells. J. Biol. Chem. 261, 4071–4075.Google Scholar
  16. 16.
    Katada, T., Kusakabe, K., Oinuma, M., and Ui, M. (1987) A novel mechanism for the inhibition of adenylate cyclase via inhibitory GTPbinding proteins. Calmodulin-dependent inhibition of the cyclase catalyst by the B’-subunits of GTP-binding proteins. J. Biol. Chem. 262, 11897–11900.Google Scholar
  17. 17.
    Asano, T., Ogasawara, N., Kitajima, S., and Sano, M. (1986) Interaction of GTP-binding proteins with calmodulin. FEBS Lett. 203, 135–138.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • D. M. F. Cooper
    • 1
  • K. K. Caldwell
    • 1
  • E. Perez-Reyes
    • 1
  • M. K. Ahlijanian
    • 1
  • W. Schlegel
    • 2
  1. 1.University of Colorado Health Sciences CenterDenverUSA
  2. 2.University of GenevaGenevaSwitzerland

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