Calcineurin regulatable adenylate cyclase

Details Calcineurin regulatable adenylate cyclase Calcineurin regulatable adenylate cyclase

1997-08-13

2000-07-18

Wax, Robert A.

Chemistry: molecular biology and microbiology

Micro-organism, per se ; compositions thereof; proces of...

Bacteria or actinomycetales; media therefor

4353201, 435325, 435369, 536 232, C12N 120, C12N 1500, C12N 500, C07H 2104

Patent

active

06090612&

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the control of cellular metabolic process by adenylate cyclase.
Cells of multi-cellular organisms may be metabolically affected by external factors, which are usually chemical. Hormones are a well-known example of such chemical factors. Generally the external chemical factors interact with a specific receptor located on the membrane of the targeted cell. The binding event of the factor to its receptor may induce alterations in cellular metabolism via a "secondary messenger" mediator.
One of the key "secondary messengers" is cyclic AMP (cAMP) (see Sutherland, Science 177:401-407 (1972)). Cyclic AMP is produced from ATP through the action of an enzyme, adenylate cyclase. It is now known that adenylate cyclase activity may be affected by a factor/receptor binding event transmitted through an associated G protein.
Alteration of the intracellular concentration of cAMP affects many cellular reactions. For example, an increase in cAMP intracellular concentration stimulates the activity of protein kinases (enzymes that transfer terminal phosphate groups from ATP to specific sites on targeted proteins). The action of the protein kinases changes the activity or function of its substrate.
For a general review of cAMP and secondary messenger systems reference is made to "Molecular Cell Biology", Darnell et al, 1986, Chapter 16, incorporated herein by reference.
Further investigations of cAMP as a secondary messenger revealed that an alteration in cAMP intracellular concentration was caused by the interaction of several different external factors with their distinct receptors. Further, it was found that different receptors were associated with their own particular G-protein intermediary which was itself associated with adenylate cyclase. More recent investigations have shown that there are in fact different types (isoenzymes) of adenylate cyclase, which display considerable regulatory diversity.
To date eight distinct isoenzymes of adenylate cyclase have been identified and described in the literature. The complete cDNA sequences are known for isoenzymes types 1 to 8. A review of the current understanding and knowledge of the known adenylate cyclase isoenzymes is set out in Pieroni et al, Current Opinion in Neurobiology 3:345-351 (1993); Kerwin Jr in Annual Reports in Medicinal Chemistry, Section VI, Chapter 29, Pages 287-295 (ed Venuti), (1994) and Premont, Methods in Enzymology 238:116-127 (1994).
A summary of the regulation of the known isoenzymes of adenylate cyclase is set out below in Table 1.


TABLE 1 ______________________________________ cAMP Isoenzyme Regulated by concentration ______________________________________ 1 Ca.sup.2+ /CaM .uparw. .beta. .gamma. dimer .dwnarw. 2 G.sub.xi + PKC .uparw. .beta. .gamma. dimer .uparw. PKC .uparw. 3 Ca.sup.2+ /CaM .uparw. 4 .beta. .gamma. dimer .uparw. 5 Ca.sup.2+ .dwnarw. 6 Ca.sup.2+ .dwnarw. ______________________________________ CaM = calmodulin PCK = protein Kinase C
It has now been found, for the first time, that the protein phosphatase calcineurin regulates an adenylate cyclase isoenzyme.
It has further now been found that the isoenzyme regulated by calcineurin is a novel previously uncharacterised adenylate cyclase isoenzyme. The novel isoenzyme of the present invention was originally referred to as adenylate cyclase 10 (AC10), but a review of nomenclature has now caused the novel adenylate cyclase to be referred to as adenylate cyclase 9 (AC9). To avoid confusion with the different isoenzyme known before the nomenclature revision as "adenylate cyclase 9", the novel adenylate cyclase of the present invention will herein simply be referred to as "AC".
The nucleotide sequence encoding for AC has been identified, cloned and sequenced (see Example 2). The nucleotide sequence encoding for AC is given in SEQ ID No 1. The sequence is also accessible in the Genbank.TM. database under accession No. MMU30602 and in the EMBL database under accession No. Z50190.
The present i

REFERENCES:
Antoni et al., Ca2+/calcineurin inhibition of adenylyl cyclase in mouse anterior pituitary corticotroph tumor cells, J. Physiol, vol. 475P, 1994, pp. 137P-138P.
Shipston et al., Glucocorticoid Negative Feedback in Pituitary Corticotropes, Annals NY Academy of Sciences, vol. 746, Nov. 30, 1994, pp. 453-455.
Paterson et al., Control of a Novel Adenylyl Cyclase by Calcineurin, Biochemical & Biophysical Resrch Communications, vol. 214, No. 3, Sep. 25, 1995, pp. 1000-1008.
Antoni et al., Calcineurin Feedback Inhibition of Agonist-evoked cAMP Formation, Journal of Biological Chemistry, vol. 270, No. 47, Nov. 24, 1995, pp. 28055-28061.
Krupinski et al., Molecular Diversity in the Adenylylcyclase Family, Journal of Biological Chemistry, vol. 267, No. 34, Dec. 5, 1992, pp. 24858-24862.
Premont et al., Two members of a widely expressed subfamily of hormone-stimulated adenylyl cyclases, Proc. Natl. Acad. Sci., vol. 89, Dec. 1992, pp. 9809-9813.
Premont, Identification of Adenylyl Cyclases by Amplification Using Degenerate Primers, Methods in Enzymology, vol. 238, pp. 116-127, (1994).
Kerwin et al., Adenylate Cyclase Subtypes as Molecular Drug Targets, Annual Reports in Medicinal Chemistry, Chapter 29, pp. 287-295, (1994).
Pieroni et al., Signal Recognition and Integration by Gs-Stimulated Adenylyl Cyclases, Current Opinion in Neurobiology (1993), vol. 3, pp. 344-351.

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