Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although nitric oxide (NO) participates in development of hypersensitivity states in the spinal cord thought to underlie chronic pain, it also participates in analgesia produced by various drugs. In rats with a hypersensitivity state following peripheral nerve injury, spinal administration of an NO donor or l-cysteine alone produced no effect, whereas their combination, which yields s-nitroso-l-cysteine (SNC) powerfully reduced hypersensitivity. In the current study, we examined the ability of SNC to stimulate release of a known spinal analgesic neurotransmitter, norepinephrine (NE), as a possible mechanism of analgesic action of NO in the spinal cord. SNC (but not the NO donor alone or decomposed SNC) produced a concentration-dependent release of NE from rat spinal cord synaptosomes. The d-isomer of SNC was less potent than the l-isomer, and the effect of SNC was partially blocked by l-, but not d-leucine, implicating an interaction with the l-amino acid transporter. SNC-induced NE release was partially Na(+) dependent, but largely Ca(2+) independent. NE uptake inhibitors partially antagonized the effect of SNC, but guanylate cyclase inhibitors were without effect. These data are therefore consistent with NO stimulating NE release in the spinal cord via reaction with thiol containing compounds, such as cysteine, entry into NE terminals via active transport, and production of both exocytotic and carrier mediated release.
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PMID:S-nitroso-l-cysteine releases norepinephrine in rat spinal synaptosomes. 1092 12

We examined the nature and regulation of the inward L-3,4-dihydroxyphenylalanine (L-DOPA) transporter in rat capillary cerebral endothelial (RBE4) cells, type 1 astrocytes (DI TNC1), and Neuro-2a neuroblastoma cells. In all three cell types, the inward transfer of L-DOPA was largely promoted through the 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid-sensitive and sodium-independent L-type amino acid transporter. Only in DI TNC1 cells was the effect of maneuvers that increase intracellular cAMP levels accompanied by increases in L-DOPA uptake. Also, only in DI TNC1 cells was the effect of the guanylyl cyclase inhibitor LY-83583 accompanied by a 65% increase in L-DOPA accumulation, whereas the nitric oxide donor sodium nitroprusside produced a 25% decrease in L-DOPA accumulation. In all three cell types, the Ca2+/calmodulin inhibitors calmidazolium and trifluoperazine inhibited L-DOPA uptake in a noncompetitive manner. Thapsigargin (1 and 3 microM) and A-23187 (1 and 3 microM) failed to alter L-DOPA accumulation in RBE4 and Neuro-2a cells but markedly increased L-DOPA uptake in DI TNC1 cells. We concluded that L-DOPA in RBE4, DI TNC1, and Neuro-2a cells is transported through the L-type amino acid transporter and appears to be under the control of Ca2+/calmodulin-mediated pathways. Astrocytes, however, are endowed with other processes that appear to regulate the accumulation of L-DOPA, responding positively to increases in intracellular Ca2+ and cAMP and to decreases in cGMP.
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PMID:Regulatory pathways and uptake of L-DOPA by capillary cerebral endothelial cells, astrocytes, and neuronal cells. 1120 29

The distinctive function of nitric oxide (NO) in biology is to transmit cellular signals through membranes and regulate cellular functions in adjacent cells. NO conveys signals as a second messenger from a cell where NO is generated to contiguous cells in two ways; one is as gaseous molecule by free diffusion resulting in an activation of soluble guanylate cyclase (NO/cGMP pathway), and another form is by binding with a molecule such as cysteine or protein thiol through S-nitrosylation (SNO pathway). Both pathways transmit much of the biological influence of NO from cell where other messenger molecules but NO are confined, through the plasma membrane to the adjacent cells. Since SNO pathway cannot utilize free-diffusion mechanism to get through the membrane as the molecular size is significantly larger than NO molecule, it utilizes amino acid transporter to convey signals as a form of S-nitrosylated cysteine (CysNO). Although S-nitrosylated glutathione (GSNO) is the molecule which act as a determinant of the total S-nitrosothiol level in cell, transnitrosylation reaction from GSNO to CysNO is an initial requirement to pass through signal through the membrane. Thus, multiplexed combination of these steps and the regulatory factors involved in this system conform and modify the outcome from stimulus-response coupling via the SNO pathway.
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PMID:Membrane transfer of S-nitrosothiols. 2137 31