sGC x GC-C

Guanylyl cyclase (GC) is an enzyme that produces 3',5'-cyclic guanosine monophosphate (cGMP), one of the two canonical cyclic nucleotides used as a second messenger for intracellular signal transduction. The GCs are classified into two groups, particulate/membrane GCs (pGC) and soluble/cytosolic GCs (sGC). In relation to the endocrine system, pGCs include hormone receptors for natriuretic peptides (GC-A and GC-B) and guanylin peptides (GC-C), while sGC is a receptor for nitric oxide and carbon monoxide. Comparing the functions of pGCs in eukaryotes, it is apparent that pGCs perceive various environmental factors such as light, temperature, and various external chemical signals in addition to endocrine hormones, and transmit the information into the cell using the intracellular signaling cascade initiated by cGMP, e.g., cGMP-dependent protein kinases, cGMP-sensitive cyclic nucleotide-gated ion channels and cGMP-regulated phosphodiesterases. Among vertebrate pGCs, GC-E and GC-F are localized on retinal epithelia and are involved in modifying signal transduction from the photoreceptor, rhodopsin. GC-D and GC-G are localized in olfactory epithelia and serve as sensors at the extracellular domain for external chemical signals such as odorants and pheromones. GC-G also responds to guanylin peptides in the urine, which alters sensitivity to other chemicals. In addition, guanylin peptides that are secreted into the intestinal lumen, a pseudo-external environment, act on the GC-C on the apical membrane for regulation of epithelial transport. In this context, GC-C and GC-G appear to be in transition from exocrine pheromone receptor to endocrine hormone receptor. The pGCs also exist in various deuterostome and protostome invertebrates, and act as receptors for environmental, exocrine and endocrine factors including hormones. Tracing the evolutionary history of pGCs, it appears that pGCs first appeared as a sensor for physicochemical signals in the environment, and then evolved to function as hormone receptors. In this review, the author proposes an evolutionary history of pGCs that highlights the emerging role of the GC/cGMP system for signal transduction in hormone action.

We previously showed that hepatic nitric oxide regulates net hepatic glucose uptake (NHGU), an effect that can be eliminated by inhibiting hepatic soluble guanylate cyclase (sGC), suggesting that the sGC pathway is involved in the regulation of NHGU. The aim of the current study was to determine whether hepatic cyclic guanosine monophosphate (cGMP) reduces NHGU. Studies were performed on conscious dogs with transhepatic catheters. A hyperglycemic-hyperinsulinemic clamp was established in the presence of portal vein glucose infusion. 8-Br-cGMP (50 µg/kg/min) was delivered intraportally, and either the glucose load to the liver (CGMP/GLC; n = 5) or the glucose concentration entering the liver (CGMP/GCC; n = 5) was clamped at 2× basal. In the control group, saline was given intraportally (SAL; n = 10), and the hepatic glucose concentration and load were doubled. 8-Br-cGMP increased portal blood flow, necessitating the two approaches to glucose clamping in the cGMP groups. NHGU (mg/kg/min) was 5.8 ± 0.5, 2.7 ± 0.5, and 4.8 ± 0.3, whereas the fractional extraction of glucose was 11.0 ± 1, 5.5 ± 1, and 8.5 ± 1% during the last hour of the study in SAL, CGMP/GLC, and CGMP/GCC, respectively. The reduction of NHGU in response to 8-Br-cGMP was associated with increased AMP-activated protein kinase phosphorylation. These data indicate that changes in liver cGMP can regulate NHGU under postprandial conditions.