Adenylyl cyclases in the digestive system

Abstract

Adenylyl cyclases (ACs) are a group of widely distributed enzymes whose functions are very diverse. There are nine known transmembrane AC isoforms activated by Gαs. Each has its own pattern of expression in the digestive system and differential regulation of function by Ca2+ and other intracellular signals. In addition to the transmembrane isoforms, one AC is soluble and exhibits distinct regulation. In this review, the basic structure, regulation and physiological roles of ACs in the digestive system are discussed.

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…There was a notable absence of AC1 and AC8, consistent expression for AC6 and AC9, and a more mixed expression pattern of the other AC isoforms throughout the nephron (Rieg and Kohan, 2014). The distribution of AC isoforms in the digestive system was also reviewed (Sabbatini et al, 2014). Similar to the other organs/cells reported, mRNA for multiple ACs were found in hepatocytes and cholangiocytes (Strazzabosco et al, 2009), as well as in the pancreatic acini and duct (Sabbatini et al, 2013).…”

“…In view of the lack of isoform-specific inhibitors and isoform-specific antibodies, knockout and overexpression studies with mice have driven most of our current understanding (Table 4). Several reviews delve more deeply into the exact roles for different AC isoforms in a variety of systems Xia and Storm, 2012;Guellich et al, 2014;Nicol and Gaspar, 2014;Rieg and Kohan, 2014;Sabbatini et al, 2014;Lee, 2015). Overall, our knowledge on the role of specific AC isoforms in human pathophysiology is still very limited.…”

Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus

“…Therefore, to isolate a potential role of AC6 in kidney and CD PCs, the main "target" cell for Li + effects (24), we generated a condition- al mouse model with AC6 deletion controlled by AQP2-dependent Cre recombinase expression (25). After several attempts with antibodies from various commercial sources, we identified an antibody that, in cortex homogenates from WT mice, detected AC6 as a smear centered at 150 kDa (26,27). No signal was detectable in AC6 -/-mice, demonstrating for the first time to our knowledge specificity of an AC6 antibody in Western blots (Figure 2A).…”

Investigation of cAMP microdomains as a path to novel cancer diagnostics

“…In mammals, cAMP controls a wide range of cellular processes and is present in every cell type and organ. cAMP is synthesized from ATP by a class of enzymes called adenylyl cyclases (ACs), which are encoded by 10 different genes (ADCY1–10) [1]. ACs 1–9 encode for proteins with a fairly similar structure in that all of them are transmembrane proteins (tmACs) and reside principally at the plasma membrane and endosomes making these ACs well suited to respond to extracellular signals.…”

“…In many ways, tmACs function to coordinate cells within a tissue. Most tmACs are principally regulated by G protein coupled receptors via direct stimulation by heterotrimeric G proteins either by direct interaction between tmACs and the G s subunit or subunits [1]. Regulation of tmACs can be divided into four groups: Group 1, Ca 2+ /calmodulin-stimulated AC1, AC3, and AC8; Group 2, G -stimulated and Ca 2+ -insensitive AC2, AC4, and AC7; Group 3, G i/Ca 2+ /PKA-inhibited, AC5 and AC6; and Group 4, forskolin/Ca 2+ / G -insensitive, AC9 [1].…”