Soluble Adenylyl Cyclase Defines a Nuclear cAMP Microdomain in Keratinocyte Hyperproliferative Skin Diseases

Abstract

Cyclic adenosine monophosphate (cAMP) is a nearly ubiquitous signaling molecule important for numerous signaling pathways in human skin. We studied a novel class of mammalian adenylyl cyclase, the soluble adenylyl cyclase (sAC). We examined sAC localization in normal human skin and found it to be present in keratinocytes, melanocytes, mononuclear cells, eccrine ducts, and nerves. In normal skin, sAC keratinocyte staining was evenly distributed throughout the cell. However, in certain hyperproliferative disorders of the skin, including psoriasis, verruca vulgaris, and SCCIS on sun-damaged skin, sAC keratinocyte staining was predominantly nuclear. In contrast, in other hyperproliferative disorders, such as basal cell carcinoma, sAC staining was similar to normal human skin. Using a model of epithelial differentiation, we established that sAC migrates into the nucleus when differentiated cells are induced to reenter the cell cycle. Previous work had determined that nuclear sAC activates the cAMP-response-element-binding (CREB) transcription factor, and we found that in psoriasis lesions, nuclear sAC occurs concomitantly with activation of CREB. Hence, sAC may play a role in the pathogenesis of certain hyperproliferative skin disorders via modulation of gene expression.

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

“…Pharmacological sAC modulation has potential therapeutic applications (19)(20)(21)39), and because artificially manipulating the natural activator bicarbonate is problematic in physiological systems, sAC-selective modulators would facilitate in vivo studies. In tmAC, the space corresponding to the hydrophilic sAC BBS between Arg176 (Asn in tmAC) and Lys95 is blocked by a hydrophobic residue (Leu438 in tmACV-C 1 , interacting with Phe338).…”

“…In mammals, sAC acts as a CO 2 /HCO 3 − /pH sensor in processes such as sperm activation (15), acid-base homeostasis (16), and various metabolic responses (10,17,18). sAC has also been implicated in skin and prostate cancer and as a target for male contraceptives (19)(20)(21).…”

Soluble Adenylyl Cyclase in Vascular Endothelium

“…sAC has been reported to be involved in transmembrane adenylyl cyclases-independent cAMP signaling inside the mammalian cell nucleus, affecting CREB phosphorylation via PKA. 37,38 Our experiments, including a CRE reporter vector and the sAC-specific inhibitor KH7, revealed potent inhibition of CRE-dependent promoter activation on sAC depletion. Previous studies have demonstrated that KH7 effectively inhibits sAC enzyme activity at concentrations of 10 to 30 μmol/L, whereas transmembrane adenylyl cyclases and soluble guanylyl cyclases remained unaffected.…”

Established and potential physiological roles of bicarbonate-sensing soluble adenylyl cyclase (sAC) in aquatic animals

“…Moreover, nuclear sAC has been suggested to determine the aggressiveness of certain skin and prostate cancers (Flacke et al, 2013;Magro et al, 2012a;Magro et al, 2012b;Zippin et al, 2010). In the heart, sAC controls mitochondria-dependent apoptosis in both coronary endothelial cells (Kumar et al, 2009) and cardiomyocytes (Appukuttan et al, 2012) (reviewed in Chen et al, 2012b).…”