Post by Max on Jun 12, 2005 18:57:24 GMT -5
In the central nervous system, glutamate serves as an excitatory neurotransmittor. Glutamate is also the precursor of the inhibitory neurotransmittor GABA, as well as glutamine, a potential mediator of hyperammonemic neurotoxicity [1].
Altered synthesis of GABA
Modulation of Sp1 activity by nuclear receptors is a novel mechanism by which fat-soluble hormones regulate gene expression. Northern blot analyses showed that in addition to urokinase, after induction of RARs, RA up-regulates GC-rich region-dependent mRNA expression of transglutaminase, TGF beta 1, and types I and II TGF beta receptors [2]. Glutamic acid decarboxylase (GAD) 65 is one of two homologous proteins responsible for the synthesis of gamma-aminobutyric acid, the most ubiquitous inhibitory neurotransmitter. Gel-shift assays and reporter gene assays suggest that Sp1 can bind to a region devoid of consensus Sp1 binding sites that are found on the GAD promoter [3].
Hoffman la Roche itself has admitted to the findings of a significantly increased alkaline phosphatase [0]. The ubiquitous enzyme TNAP (tissue non-specific alkaline phosphatase) is found in numerous tissues such as liver, kidney and bone, but little attention has been paid to its expression and role in the brain. Observations in TNAP-KO mice, which analyzed the role of this enzyme in osteogenesis, had suggested that TNAP might be involved in GABA neurotransmission. Apart from its presence in endothelial cells, there is a specific and strong alkaline phosphatase (AP) activity in the neuropile, matching the pattern of thalamo-cortical innervation in layer 4 of the primate sensory cortices (visual, auditory and somatosensory). Such a pattern is also evident in rodents and carnivores, making AP a powerful marker of primary sensory areas. Remarkably, AP activity is regulated by sensory experience as demonstrated by monocular deprivation paradigms in monkeys. The areal and laminar distribution of AP activity matches that of the GAD(65), the GABA synthesizing enzyme found in presynatic terminals. As our electron microscopic investigations indicate that AP is found at the neuronal membranes and in synaptic contacts, it is proposed that the neuronal AP isoform (NAP), may be a key enzyme in regulating neurotransmission and could therefore play an important role in developmental plasticity and activity-dependent cortical functions [5].
The role of uPAR in the adult brain is unknown. Mice with a targeted mutation of the gene encoding urokinase plasminogen activator receptor (uPAR), a key component in HGF/SF activation and function, have decreased levels of HGF/SF and a 50% reduction in neocortical GABAergic interneurons at embryonic and perinatal ages [6].
GABA catabolism
Possible interactions between massive doses of retinoic acid and GABA catabolic enzyme succinic semialdehyde dehydrogenase (SSADH) are unkown.
glutamate decarboxylase (GAD): GAD2 (GAD65) 10p11.23
aldehyde dehydrogenase 5 family, member A1 (succinate-semialdehyde dehydrogenase) ALDH5A1
glutamate dehydrogenase 1 (GLUD1) 10q23.3
-binding sites for AP1, AP2 and SP1
Altered synthesis of GABA
Modulation of Sp1 activity by nuclear receptors is a novel mechanism by which fat-soluble hormones regulate gene expression. Northern blot analyses showed that in addition to urokinase, after induction of RARs, RA up-regulates GC-rich region-dependent mRNA expression of transglutaminase, TGF beta 1, and types I and II TGF beta receptors [2]. Glutamic acid decarboxylase (GAD) 65 is one of two homologous proteins responsible for the synthesis of gamma-aminobutyric acid, the most ubiquitous inhibitory neurotransmitter. Gel-shift assays and reporter gene assays suggest that Sp1 can bind to a region devoid of consensus Sp1 binding sites that are found on the GAD promoter [3].
Hoffman la Roche itself has admitted to the findings of a significantly increased alkaline phosphatase [0]. The ubiquitous enzyme TNAP (tissue non-specific alkaline phosphatase) is found in numerous tissues such as liver, kidney and bone, but little attention has been paid to its expression and role in the brain. Observations in TNAP-KO mice, which analyzed the role of this enzyme in osteogenesis, had suggested that TNAP might be involved in GABA neurotransmission. Apart from its presence in endothelial cells, there is a specific and strong alkaline phosphatase (AP) activity in the neuropile, matching the pattern of thalamo-cortical innervation in layer 4 of the primate sensory cortices (visual, auditory and somatosensory). Such a pattern is also evident in rodents and carnivores, making AP a powerful marker of primary sensory areas. Remarkably, AP activity is regulated by sensory experience as demonstrated by monocular deprivation paradigms in monkeys. The areal and laminar distribution of AP activity matches that of the GAD(65), the GABA synthesizing enzyme found in presynatic terminals. As our electron microscopic investigations indicate that AP is found at the neuronal membranes and in synaptic contacts, it is proposed that the neuronal AP isoform (NAP), may be a key enzyme in regulating neurotransmission and could therefore play an important role in developmental plasticity and activity-dependent cortical functions [5].
The role of uPAR in the adult brain is unknown. Mice with a targeted mutation of the gene encoding urokinase plasminogen activator receptor (uPAR), a key component in HGF/SF activation and function, have decreased levels of HGF/SF and a 50% reduction in neocortical GABAergic interneurons at embryonic and perinatal ages [6].
GABA catabolism
Possible interactions between massive doses of retinoic acid and GABA catabolic enzyme succinic semialdehyde dehydrogenase (SSADH) are unkown.
glutamate decarboxylase (GAD): GAD2 (GAD65) 10p11.23
aldehyde dehydrogenase 5 family, member A1 (succinate-semialdehyde dehydrogenase) ALDH5A1
glutamate dehydrogenase 1 (GLUD1) 10q23.3
-binding sites for AP1, AP2 and SP1