Cyclic AMP, at the hub of the cystic cycle

Abstract

EDITORIALCyclic AMP, at the hub of the cystic cycle Half a century after its discovery, new roles for adenosine 3 ,5 -cyclic monophosphate (cAMP) continue to be discovered. The article by Belibi et al [1] in this issue of Kidney International, implicates cAMP in the pathogenesis of autosomal-dominant and recessive polycystic kidney diseases (ADPKD and ARPKD) and provides a target for the pharmacologic treatment of these disorders.Cyclic AMP is a ubiquitous and versatile second messenger. Extracellular ligands bind to G proteincoupled receptors (GPCR) that positively (Gs) or negatively (Gi) regulate closely associated adenylyl cyclases (ACs). Cyclic AMP levels are controlled within specific cellular compartments by the activity of cAMP phosphodiesterases (PDEs), themselves subject to complex regulatory mechanisms. Maximal rates of degradation by PDEs exceed those of synthesis by ACs, pointing to the importance of PDEs in the regulation of cAMP signaling. Cyclic AMP may exit the cells by an energy-dependent transport mechanism, but in most cells efflux does not have a major effect on cAMP levels. Biological effects of cAMP are mediated by protein kinase A (PKA), cyclic nucleotide gated cation channels, and guanine nucleotide exchange factors. PKA is targeted to specific cellular compartments by A kinase-anchoring proteins (AKAPs). The specificity of cAMP signaling is achieved by the extraordinary diversity of ACs, PDEs, PKAs, and AKAPs. It also depends on cell-type specific cross-talk with other signaling systems, such as mitogenactivated protein kinase/extracellular-regulated kinase (MAPK/ERK) cascades that couple growth factor receptors and Ras to cell proliferation. They consist of three protein kinases acting in series, a MAP kinase kinase kinase (MAPKKK), which activates a MAP kinase kinase (MAPKK or MEK), which phosphorylates a MAP kinase (MAPK or ERK). In the ERK1/2 cascade, the Raf family of serine/threonine protein kinases (A-Raf, B-Raf, and Raf-1) function as MAPKKK. Activated PKA catalytic subunits and ERKs can translocate to the nucleus where they phosphorylate transcription factors. Calcium in intracellular compartments ([Ca 2+ ] i ) that may be directly affected by polycystic kidney disease (PKD)-causing genetic alterations can regulate positively and negatively cAMP and MAPK signaling.

Identification of a Forskolin-Like Molecule in Human Renal Cysts

“…Second, relatively high levels of forskolin-like activity were discovered in the cyst fluid of a 2-wk-old infant with ARPKD. cAMP is a major growth factor in PKD progression through its effects to stimulate fluid secretion into the cysts and its mitogenic effect on mural epithelial cells (23). Recent studies of hereditary polycystic disease in rodents showed that suppres- Figure 6.…”

Reducing Polycystic Liver Volume in ADPKD

“…A prospective, randomized, crossover, double-blind, placebo-controlled study showed that 6 months of octreotide therapy limited kidney volume growth versus placebo in 12 patients with ADPKD (6) possibly through inhibition of cAMP production and activity (7). To assess the treatment effect on polycystic liver, in this post hoc analysis of the above study we primarily compared liver volume changes during octreotide and placebo therapy in the same population.…”

Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: Summary statement of a First National Institutes of Health/Office of Rare Diseases conference

“…Increased intracellular cAMP is a common feature of both ARPKD and ADPKD renal cells 22 (Figure). Renal cAMP concentrations are increased in the pck rat (a model in which the rat orthologue of PKHD1 is disrupted), as well as the pcy muse (modeling human nephronophthisis) and the Pkd2 WS25 mouse (modeling human ADPKD).…”