ASSIGNMENT

Classification of cNMP



Classification of cNMP

Question 1

Signal transduction pathways control many critical cellular processes, including chemotaxis, differentiation, proliferation, and apoptosis. For example, signal transduction pathways are necessary for bacterial pathogens to sense and respond to host environments, cellular differentiation during embryogenesis, conductance of nerve impulses, and cell cycle control. Disruption of these pathways can result in neoplasia, arteriosclerosis, neurological and developmental abnormalities, and cell death. The most common mechanisms of signal transduction include the phosphorylation or dephosphorylation of effector proteins by kinases and phosphatases, respectively, and the production of second messengers. Cyclic nucleotides were first recognized as second messengers 40 years ago. Such diverse molecules as (p)ppGpp, Ca2+, inositol triphosphate, and diacylglycerol have also been recognized as second messengers since then (Bell, 1990).

The cyclic nucleotides adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) are key universal second messengers, mediating cellular functions in organisms as phylogenetically diverse as Escherichia coli and Homo sapiens. Intracellular concentrations of cyclic nucleotides (cNMPs) are controlled by regulation of their relative rates of synthesis, excretion, and degradation (Botsford and Harman 1992; Tang et al. 1998). The nucleotide cyclases (adenylyl and guanylyl cyclase), the cNMP phosphodiesterases, and the cyclic nucleotide effector proteins (cNMP-binding proteins) have been particularly intense areas of signal transduction research, providing detailed studies of these proteins. The molecular mechanisms of cNMP export, however, are currently unknown.

The cyclic nucleotide-binding proteins identified in prokaryotes consist of a small group of orthologous cAMPreceptor proteins (CRP) present only in gram-negative bacteria of the gamma subdivision of the Proteobacteria. CRP is a global regulator belonging to the CRP/FNR (Fumarate and NitrateReduction) family of prokaryotic transcription regulators. The CRP-cAMP complex is involved in positive as well as negative regulation of a wide variety of promoters.

Three functional classes of cyclic nucleotide-binding proteins have been described in eukaryotes: kinases, channels, and guanine nucleotide exchange factors (GEFs) (Chen, 1994). Cyclic nucleotide-dependent kinases have long been considered the primary effectors that mediate cellular responses to changes in intracellular cNMP concentrations. Both cAMP-dependent kinases (cAK) and cGMP-dependent kinases (cGK) have been described in many eukaryotic species. A significant number of cyclic nucleotide-gated and cyclic nucleotide-modulated ion channels are also involved in many cell functions in eukaryotes. In addition, mammalian cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs) that selectively activate Rap1A (a Ras family G protein) were recently described.

All of these cNMP-binding proteins (cAK and cGK, cNMP-regulated channels, cAMP-GEFs, and CRP) share sequence homology in their ...