ABSTRACT
Nearly two decades ago, Joe Coyle published a single-authored review with the provocative title, The Nagging Question of the Function of N-Acetylaspartylglutamate (Coyle, 1997). In this review, Coyle documented NAAG's localization to subpopulations of glutamatergic, cholinergic, GABAergic, and noradrenergic neurons, Ca(2+)-dependent release, mGlu3 receptor agonist and NMDA receptor antagonist activity, and cleavage by the glial enzyme glutamate carboxypeptidase II (GCPII). However, at the time of his review, NAAG's physiological function as a neurotransmitter remained elusive. Ironically his review was published months following the discovery of the first potent and selective GCPII inhibitor, 2-(phosphonomethyl)pentanedioc acid (2-PMPA) (Jackson et al., 1996). Over the ensuing decades, over a dozen independent laboratories used 2-PMPA and other GCPII inhibitors to elucidate two distinct neurotransmitter functions for NAAG. Under basal conditions, when GCPII activity is relatively low, intact NAAG dampens synaptic activity via presynaptic mGlu3 receptor activation and NMDA receptor blockade. However, under stimulated conditions, NAAG release and GCPII activity are enhanced resulting in excess glutamate generation, activating NMDA and other glutamate receptors, often pathologically. Diverse classes of GCPII inhibitors have been synthesized and shown to increase NAAG, decrease glutamate, and provide robust efficacy in many disease models wherein abnormal glutamatergic transmission is presumed pathogenic. In addition, over the past 20 years, basic questions regarding NAAG's synthesis, packaging into vesicles, and receptor selectivity profile have been eloquently elucidated. The purpose of this chapter is to summarize these advances and the promise of regulating NAAG metabolism through GCPII inhibition as a therapeutic strategy.
Subject(s)
Dipeptides/metabolism , Glutamate Carboxypeptidase II/antagonists & inhibitors , Glutamic Acid/metabolism , Animals , Antigens, Surface , Humans , Neuroglia/metabolism , Neurotransmitter Agents/metabolismABSTRACT
O treinamento muscular inspiratório (TMI) tem demonstrado efeitos positivos na melhora da função muscular inspiratória, porém seus efeitos sobre a intolerância ao esforço e a qualidade de vida ainda precisam ser esclarecidos. Este estudo visou avaliar...
Inspiratory muscle training (IMT) has shown beneficial effects concerning inspiratory muscle function, but its effects on exercise intolerance and quality of life are not clearly established...
Subject(s)
Humans , Male , Female , Breathing Exercises , Pulmonary Disease, Chronic Obstructive/rehabilitation , Exercise Therapy , Respiratory MusclesABSTRACT
Notochord from several Anura Amphibia embryos was investigated by cytochemical study. A green fluorescence was observed, indicating a catecholamine storage in the notochord, during a precise time of their development. A stimulation of the mesoblast area by catecholamine is suggested by the analogy between the catecholamine chordal distribution and the adenyl-cyclase activity of the chordo-mesoderm. This stimulation would be followed by a cAMP production directing the PGC migration. Treatment by L-dopa increases fluorescence in the notochord. Reserpine and alpha-methyl-paratyrosine decreases the notochord fluorescence, either by stocked catecholamine depletion in the case of reserpine, or by inhibition of their synthesis by alpha-methyl-para-tyrosine.
