Involvement of Cyclic GMP and Protein Kinase G in the Regulation of Apoptosis and Survival in Neural Cells

Abstract

Our current understanding of nitric oxide (NO), cyclic GMP (cGMP) and protein kinase G (PKG) signaling pathways in the nervous systems has its origins in the early studies conducted on vascular tissues during the late 1970s and early to mid-1980s. The pioneering research into the NO/cGMP/PKG pathway in blood vessels conducted by the laboratories of Drs. Ferid Murad, Louis Ignarro and Robert Furchgott ultimately led to the awarding of the 1998 Nobel Prize in Physiology or Medicine to these three scientists. On the basis of further pioneering studies by Drs. John Garthwaite, Solomon Snyder, Steven Vincent and many other neuroscientists during the late 1980s and throughout the 1990s, it became recognized that NO serves as a neurotransmitter/neuromodulator in the central and peripheral nervous systems and that certain neural cells possess a cGMP signaling pathway similar to that in vascular smooth muscle cells. Although NO (at high concentrations) is toxic and thought to participate in neuronal cell death during stroke and neurodegenerative diseases (e.g. amyotrophic lateral sclerosis, Alzheimer’s disease, HIV dementia and Parkinson’s disease), recent evidence suggests that NO at low physiological concentrations can act as an antiapoptotic/prosurvival factor in certain neural cells (e.g. PC12 cells, motor neurons and neurons of dorsal root ganglia, hippocampus and sympathetic nerves). The antiapoptotic effects of NO are mediated, in part, by cGMP and a downstream target protein, PKG. Other cGMP-elevating factors (e.g. atrial and brain natriuretic peptides) and direct PKG activator (e.g. 8-bromo-cGMP) also have antiapoptotic effects which have been quantified by the new capillary electrophoresis with laser-induced fluorescence detector technology. Inhibition of soluble guanylyl cyclase and lowering of basal cGMP levels cause apoptosis in unstressed neural cells (NG108-15 and N1E-115 cells). The cGMP/PKG pathway appears to play an essential role in preventing activation of a proapoptotic pathway, thus promoting neural cell survival.

Natriuretic Peptide Receptor A as a Novel Anticancer Target

“…Both ANP and brain natriuretic peptide (BNP) signal through NPRA by increasing cyclic guanosine 3 ¶,5 ¶-monophosphate (cGMP) and activating cGMP-dependent protein kinase (PKG). Activated PKG in turn up-regulates expression of genes encoding ion transporters and transcription factors, which together affect cell growth, apoptosis, proliferation, and inflammation (9)(10)(11).…”

Cisplatin alters nitric oxide synthase levels in human ovarian cancer cells: involvement in p53 regulation and cisplatin resistance

“…Furthermore, basal activity of soluble guanylyl cyclase (sGC), an intracellular receptor for nitric oxide (NO), suppresses apoptosis in ovarian cancer cells, partly via inhibition of p53 accumulation and activation (Fraser et al, 2006). We hypothesised that basal sGC activity and regulation of p53 may depend on endogenous NO formed by one of the three NO synthases (NOSs), eNOS (also called NOS3), iNOS (also called NOS2), or nNOS (also called NOS1) and that resistance to CDDP in ovarian cancer cells may involve altered expression of the NOSs.At high concentrations (typically 4100 mM), NO donors generate toxic concentrations of NO (e.g., 4100 nM), inducing apoptosis in many mammalian cells (Fiscus, 2002;Fiscus et al, 2002), including cancer cells (Wink et al, 1998). However, NO at lower, more physiological levels (e.g., 1 -20 nM) often has the opposite effect, preventing (or attenuating) the onset of apoptosis in many mammalian cells, including lung fibroblasts (Wink et al, 1993), human B lymphocytes (Mannick et al, 1994), and many normal and transformed neural cells (Fiscus, 2002;Fiscus et al, 2002).…”

“…At high concentrations (typically 4100 mM), NO donors generate toxic concentrations of NO (e.g., 4100 nM), inducing apoptosis in many mammalian cells (Fiscus, 2002;Fiscus et al, 2002), including cancer cells (Wink et al, 1998). However, NO at lower, more physiological levels (e.g., 1 -20 nM) often has the opposite effect, preventing (or attenuating) the onset of apoptosis in many mammalian cells, including lung fibroblasts (Wink et al, 1993), human B lymphocytes (Mannick et al, 1994), and many normal and transformed neural cells (Fiscus, 2002;Fiscus et al, 2002).…”

“…However, other studies focusing on ovarian cancer have shown that overexpression of iNOS correlates with increased apoptosis (Son and Hall, 2000;Rieder et al, 2001). Thus, endogenous NO may contribute to either anti-apoptotic or pro-apoptotic effects in cancer cells, most likely depending on cell type, local NO levels, source of NO production, and other conditions (e.g., concurrent overproduction of superoxide anion, which can combine with NO to form the toxic prooxidant peroxynitrite) (Fiscus, 2002;Fiscus et al, 2002).…”

“…However, NO at lower, more physiological levels (e.g., 1 -20 nM) often has the opposite effect, preventing (or attenuating) the onset of apoptosis in many mammalian cells, including lung fibroblasts (Wink et al, 1993), human B lymphocytes (Mannick et al, 1994), and many normal and transformed neural cells (Fiscus, 2002;Fiscus et al, 2002). In most cells, the anti-apoptotic effects of low-level NO are attributed to the stimulation of sGC with subsequent elevation of cyclic guanosine monophosphate (cGMP) levels and increased activation of protein kinase G (PKG).…”