NO-cGMP Signaling and Regenerative Medicine Involving Stem Cells |
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Authors: | K S Madhusoodanan Ferid Murad |
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Institution: | (1) The Brown Foundation Institute of Molecular Medicine, University of Texas Houston Health Science Center, 1825 Pressler street, Houston, TX 77030, USA;(2) Department of Integrative Biology and Pharmacology, University of Texas Medical School at Houston, 6431 Fannin Street, Houston, TX 77030, USA |
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Abstract: | Nitric oxide (NO) is a short lived diatomic free radical species synthesized by nitric oxide synthases (NOS). The physiological
roles of NO depend on its local concentrations as well as availability and the nature of downstream target molecules. At low
nanomolar concentrations, activation of soluble guanylyl cyclase (sGC) is the major event initiated by NO. The resulting elevation
in the intracellular cyclic GMP (cGMP) levels serves as signals for regulating diverse cellular and physiological processes.
The participation of NO and cGMP in diverse physiological processes is made possible through cell type specific spatio-temporal
regulation of NO and cGMP synthesis and signal diversity downstream of cGMP achieved through specific target selection. Thus
cyclic GMP directly regulates the activities of its downstream effectors such as Protein Kinase G (PKG), Cyclic Nucleotide
Gated channels (CNG) and Cyclic nucleotide phosphodiesterases, which in turn regulate the activities of a number of proteins
that are involved in regulating diverse cellular and physiological processes. Localization and activity of the NO-cGMP signaling
pathway components are regulated by G-protein coupled receptors, receptor and non receptor tyrosine kinases, phosphatases
and other signaling molecules. NO also serves as a powerful paracrine factor. At micromolar concentrations, NO reacts with
superoxide anion to form reactive peroxinitrite, thereby leading to the oxidation of important cellular proteins. Extensive
research efforts over the past two decades have shown that NO is an important modulator of axon outgrowth and guidance, synaptic
plasticity, neural precursor proliferation as well as neuronal survival. Excessive NO production as that evoked by inflammatory
signals has been identified as one of the major causative reasons for the pathogenesis of a number of neurodegenerative diseases
such as ALS, Alzheimers and Parkinson diseases. Regenerative therapies involving transplantation of embryonic stem cells (ES
cells) and ES cell derived lineage committed neural precursor cells have recently shown promising results in animal models
of Parkinson disease (PD). Recent studies from our laboratory have shown that a functional NO-cGMP signaling system is operative
early during the differentiation of embryonic stem cells. The cell type specific, spatio-temporally regulated NO-cGMP signaling
pathways are well suited for inductive signals to use them for important cell fate decision making and lineage commitment
processes. We believe that manipulating the NO-cGMP signaling system will be an important tool for large scale generation
of lineage committed precursor cells to be used for regenerative therapies.
Special issue dedicated to John P. Blass. |
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Keywords: | Nitric oxide Soluble guanylyl cyclase Cyclic GMP Signaling Physiology Neurodegenerative diseases Stem cells Regenerative medicine |
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