ABSTRACT
Muscarinc receptor-mediated signaling takes part in many physiological functions ranging from complex higher nervous activity to vegetative responses. Specificity of action of the natural muscarinic agonist acetylcholine is effected by action on five muscarinic receptor subtypes with particular tissue and cellular localization, and coupling preference with different G-proteins and their signaling pathways. In addition to physiological roles it is also implicated in pathologic events like promotion of carcinoma cells growth, early pathogenesis of neurodegenerative diseases in the central nervous system like Alzheimer's disease and Parkinson's disease, schizophrenia, intoxications resulting in drug addiction, or overactive bladder in the periphery. All of these disturbances demonstrate involvement of specific muscarinic receptor subtypes and point to the importance to develop selective pharmacotherapeutic interventions. Because of the high homology of the orthosteric binding site of muscarinic receptor subtypes there is virtually no subtype selective agonist that binds to this site. Activation of specific receptor subtypes may be achieved by developing allosteric modulators of acetylcholine binding, since ectopic binding domains on the receptor are less conserved compared to the orthosteric site. Potentiation of the effects of acetylcholine by allosteric modulators would be beneficial in cases where acetylcholine release is reduced due to pathological conditions. When presynaptic function is severely compromised, the utilization of ectopic agonists can be a thinkable solution.
Subject(s)
Muscarinic Agonists/therapeutic use , Muscarinic Antagonists/therapeutic use , Nervous System Diseases/drug therapy , Nervous System Diseases/metabolism , Neurons/metabolism , Receptors, Muscarinic/metabolism , Signal Transduction/drug effects , Animals , Humans , Neurons/drug effects , Receptors, Muscarinic/drug effectsABSTRACT
Agonist-induced subcellular redistribution of G-protein coupled receptors (GPCR) and of trimeric guanine-nucleotide binding regulatory proteins (G-proteins) represent mechanisms of desensitization of hormone response, which have been studied in our laboratory since 1989. This review brings a short summary of these results and also presents information about related literature data covering at least small part of research carried out in this area. We have also mentioned sodium plus potassium dependent adenosine triphosphatase (Na, K-ATPase) and 3H-ouabain binding as useful reference standard of plasma membrane purity in the brain.
Subject(s)
Brain/metabolism , GTP-Binding Proteins/metabolism , Heterotrimeric GTP-Binding Proteins/metabolism , Hormones/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Cell Membrane/enzymology , Cell Membrane/metabolism , Cricetinae , Down-Regulation , GTP-Binding Proteins/chemistry , Heterotrimeric GTP-Binding Proteins/chemistry , Protein Multimerization , Rats , Signal Transduction/physiology , Sodium-Potassium-Exchanging ATPase/metabolism , Subcellular Fractions/metabolismABSTRACT
Many extracellular signals are at the cell surface received by specific receptors, which upon activation transduce information to the appropriate cellular effector molecules via trimeric G proteins. The G protein-mediated cascades ultimately lead to the highly refined regulation of systems such as sensory perception, cell growth, and hormonal regulation. Transmembrane signaling may be seriously deranged in various pathophysiological conditions. Over the last two decades the major experimental effort of our group has been devoted to better understanding the molecular mechanisms underlying transmembrane signaling regulated by G proteins and to the closely related process of desensitization of hormone response. This review provides general information about the basic principles of G protein-regulated transmembrane signaling as well as about our contribution to the current progress in the field.
