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Abstract
The effects of immunosuppressant blockers of calcineurin (protein phosphatase 2B) on cAMP formation and hormone release were investigated in mouse pituitary tumor (AtT20) cells. Immunosuppressants enhanced corticotropin-releasing factor- and isoproterenol-evoked cAMP production in proportion with their potency to block calcineurin. Further analysis of cAMP production revealed that intracellular Ca2+ derived through voltage-regulated calcium channels reduces cAMP formation induced by corticotropin releasing-factor or beta 2-adrenergic stimulation and that this effect of Ca2+ is inhibited by blockers of calcineurin. AtT20 cells were found to express at least three species of adenylyl cyclase mRNA-encoding types 1 and 6 as well as a novel isotype, which appeared to be the predominant species. In two cell lines expressing very low or undetectable levels of the novel cyclase mRNA (NCB20 and HEK293 cells respectively), corticotropin-releasing factor-induced cAMP formation was not altered upon blockage of calcineurin activity. These data identify calcineurin as a Ca2+ sensor that mediates the negative feedback effect of intracellular Ca2+ on receptor-stimulated cAMP production. Furthermore, the effect of calcineurin on cAMP synthesis appears to be associated with the expression of a novel adenylyl cyclase isotype, which is highly abundant in AtT20 cells.
Highlights
Calcineurin is a Ca2ϩ/calmodulinregulated protein phosphatase first discovered in brain, where it is highly abundant (0.5–1% of total protein) [1]
As [Ca2ϩ]i is known to inhibit cAMP formation in several systems [19] and because immunosuppressants enhanced CRF-induced adrenocorticotropic hormone (ACTH) release in AtT20 cells [20], we have examined the effects of immunosuppressants on CRFinduced cAMP production
No effects of cyclosporin A were found in either system. These data show that receptor-stimulated cAMP formation may be inhibited by calcineurin and that this regulation is associated with the expression of a novel adenylyl cyclase mRNA
Summary
Calcineurin (protein phosphatase 2B) is a Ca2ϩ/calmodulinregulated protein phosphatase first discovered in brain, where it is highly abundant (0.5–1% of total protein) [1]. It is well established that the major immunosuppressant compounds cyclosporin A and FK506 are potent and, with appropriate controls, specific blockers of calcineurin in leukocytes [2] and other systems [3, 4] This observation has led to the discovery that calcineurin is an essential element of the signal transduction pathway activated by the T-cell receptor [5, 6]. Ligand-operated ion channels such as the NMDA receptor [13] or the 5HT3 receptor [14] are desensitized by calcineurin Taken together, these data indicate multiple roles for calcineurin in diverse signal transduction cascades of excitable cells. The results indicate that in AtT20 cells, calcineurin inhibits CRF-induced cAMP formation and that this is associated with the expression of a novel isotype of adenylyl cyclase
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