Control of a Novel Adenylyl Cyclase by Calcineurin

doi:10.1006/bbrc.1995.2385

Biochemical and Biophysical Research Communications

Volume 214, Issue 3, 25 September 1995, Pages 1000-1008

https://doi.org/10.1006/bbrc.1995.2385 Get rights and content

Abstract

The molecular complex formed by the immunosuppressant FK506 and the immunophilin protein FKBP12 potently inhibits the Ca²⁺/calmodulin-activated protein phosphatase calcineurin. This mechanism appears to be common to all types of cell, implying that fundamental physiological modes of calcineurin regulation are exploited by immunosuppressants. The present paper describes a novel adenylyl cyclase regulated by calcineurin that contains an FKBP12-like domain and may thus constitute a physiologically relevant calcineurin docking site mimicked by immunosuppressant-immunophilin complexes. The enzyme messenger RNA is particularly enriched in the cerebral cortex, striatum and hippocampus, where it is localized to neuronal perikarya, indicative of an important role in neuronal function.

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Two other calcium-inhibitable adenylyl cyclases, Adcy5 and Adcy9, were seen at lower levels (Figure 1b). Adcy5 and Adcy6 are directly inhibited by calcium, whereas calcium inhibition of Adcy9 is calcineurin dependent.28 Adcy5 deletion in a kidney-specific Pkd2-deletion mouse model of ADPKD reduced the severity of cystic disease in association with a reduction in tissue cAMP levels,29 indicative of an important role for Adcy5 in cAMP balance in kidney epithelia.
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Adenylate cyclases can be divided into nine membrane-bound (or particulate) and one soluble adenylate cyclases (AC1-AC9). The membrane-bound adenylate cyclases are generally stimulated by Gs and inhibited by Gi and can be divided into four groups based primarily on their sensitivity and regulation by Ca2+ (Antoni et al., 1998; Paterson et al., 1995). Group I adenylate cyclases contains AC1, AC3 and AC8, which are activated by Ca2+, group II contains AC2, AC4 and AC7 which are Ca2+-insensitive, and group III consists of AC5 and AC6 which are inhibited by Ca2+.
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The chilling of adenylyl cyclase 9 and its translational potential
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A plethora of studies indicate the important role of cAMP and cGMP cascades in neuronal plasticity and memory function. As a result, altered cyclic nucleotide signaling has been implicated in the pathophysiology of mnemonic dysfunction encountered in several diseases. In the present review we provide a wide overview of studies regarding the involvement of cyclic nucleotides, as well as their upstream and downstream molecules, in physiological and pathological mnemonic processes. Next, we discuss the regulation of the intracellular concentration of cyclic nucleotides via phosphodiesterases, the enzymes that degrade cAMP and/or cGMP, and via A-kinase-anchoring proteins that refine signal compartmentalization of cAMP signaling. We also provide an overview of the available data pointing to the existence of specific time windows in cyclic nucleotide signaling during neuroplasticity and memory formation and the significance to target these specific time phases for improving memory formation. Finally, we highlight the importance of emerging imaging tools like Förster resonance energy transfer imaging and optogenetics in detecting, measuring and manipulating the action of cyclic nucleotide signaling cascades.
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Both enzymes are widely expressed in the body including neuroendocrine tissues such as the hypothalamus, the adenohypophysis and the adrenal medulla [12,48]. First cloned from pituitary tumor (AtT20) cells on the basis that cAMP responses in these cells were enhanced by inhibitors of calcineurin [17,49], AC9 is under complex regulation by multiple protein kinases and protein phosphatases [50]. However, the exact site of phosphorylation relevant for regulation by calcineurin has not been identified.
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The levels of expression of Gsα_{(short and long)}, Gα_olf and Gβ_(common) subunits, and calcium-sensitive adenylyl cyclases isoforms (AC1, 5/6, and 8) in human brain cortical and caudate membranes were quantified by western blot analysis in order to establish their contribution to the patterns of AC functioning. Both areas expressed Gsα_long (52 kDa) with values ranging from about 1400 ng/mg of membrane protein in cerebral cortex to close to 600 ng/mg of membrane protein in caudate nucleus. In contrast, Gsα_short and Gsα_olf were expressed separately, Gsα_short in cortical membranes with values around 500 ng/mg of membrane protein and Gα_olf in caudate membranes with values around 1300 ng/mg of membrane protein. Quantitative measurements of Gβ, revealed a similar expression level in cortical and caudate membranes (5444 ± 732 versus 5511 ± 394 ng/mg protein; p = 0.966). The B_max values of GTPγS-dependent [³H]-forskolin binding show the following descending order: rat striatal membranes > rat cortical membranes = human caudate membranes > human cortical membranes. Therefore, as measured immunochemically and by [³H]-forskolin binding, there seems to be a vast excess of Gsα subunits over catalytic units of AC. The highest levels of AC5/6 expression were detected in caudate membranes. AC8 was little expressed, and there were no significant differences in the relative values between both human brain regions. Finally, the levels of the AC1 isoform were significantly lower in caudate than in cortical membranes. It is concluded that these stoichiometric data contribute nonetheless to explain the significant differences observed in signalling capacities through the AC system in both human brain regions.

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Regular ArticleControl of a Novel Adenylyl Cyclase by Calcineurin

Abstract

Regular Article
Control of a Novel Adenylyl Cyclase by Calcineurin