Cyclic Nucleotides Phosphorylated Proteins And Neuronal Function

While neuroanatomy and neurophysiology were defining the unique features of the synapse as a site for cell to cell signaling in the late fifties, neurochemistry was establishing the identity and studying the biosynthetic pathways of monoamine neurotransmitters. Meanwhile, neuropsychiatry was keeping a vigilant eye on the outcome of this concerted effort with the untold hope that a genetic defect in neurotransmitter metabolism would ac count for the pathogenesis of certain psychiatric ill nesses. Thus, when neurochemists in the early sixties began to study the feasibility of measuring the metabolism of brain neurotransmitters in vivo, clinical biochemists eagerly adopted these methods to their needs and sought to verify whether inborn errors of transmitter biogenesis were a cause for at least certain forms of depression, mania and schizophrenia. Undoubtedly, it is still too early to evaluate the outcome of these studies. However, current opinion holds that gross inborn errors in transmitter metabolism do not anpear to be operative as a primary cause of psychia tric disorders. Though monoamine metabolism appears to be defective in certain groups of psychiatric disorders, the cause of these changes can at best be associated with changes in patterns of neuronal firing. It is generally believed that these persistent changes are determined by a number of unknown factors operative in various psychia tric illnesses. In the attempt to identify the molecular nature of these unknown factors, the focus of current research is directed toward transmitter receptors.

This is the book of papers from the Second International Workshop on Brain Phosphoprotein function held in Utrecht. Partial Contents: Protein Phosphorylation and Polyphosphoinositide Metabolism; Ligand-stimulated turnover of inositol lipids in the nervous system; The role of inositol phosphates in intracellular calcium mobilization; Possible roles of protein kinase C in signal transduction in nervous tissues; Polyphosphoinositides, phosphoproteins and receptor function in rabbit iris smooth muscles; Pharmacological aspects of the inositide response in the central nervous system: the muscarinic acetylcholine receptor; Ion Channels: Modulation of ion channels by Calcium activated protein phosphorylation: a biochemical mechanism for associative learning; Cyclic nucleotides as modulators and activators of ionic channels in the nerve cell membrane; Receptors: Phosphorylation of the nicotinic acetylcholine receptor; Molecular mechanisms involved in the desensitization of dopamine receptors in slices of corpus striatum; Growth factor activation of protein kinase C-dependent and -independent pathways of protein phosphorylation in fibroblasts; relevance to activation of protein kinase C in neuronal tissues; Plasticity: Synaptic plasticity and protein kinase C; Protein phosphorylation in the nerve growth cone; Long-term potentiation and 4-aminopyridine-induced changes in protein and lipid phosphorylation in the hippocampal slice; Phosphorylation/dephosphorylation mechanisms in coated vesicles; Cyclic nucleotide- and calcium-dependent protein phosphorylation in rat pineal gland: physiological and pharmacological regulation; Synapsin I: A review of its distribution and biological regulation.

Considers the role of protein phosphorylation in neuron-specific phenomena. Comprehensively treats the enzymes and molecular biology of phosphorylation and dephosphorylation reactions, examines evidence for the obligatory role of these reactions in neuronal function, and extensively reviews the large number of phosphorylation pathways and their interactions. Original schematic diagrams illustrate principles of the biochemical basis of cell regulation.

Showcasing the recent progresses of the field, Cyclic Nucleotide Signaling covers the major tools and methodologies used in various areas of research. The majority of the chapters are protocol oriented, with the goal of providing clear directions for laboratory use. Students and investigators new to the field will find this book particularly informative, as will scientists already actively researching nucleotide signaling.

The elucidation of the cellular and molecular bases underlying the inte grated function of the central nervous system, both in disease and in health, must ultimately come from the combined efforts of scientists from many disciplines, including biology, chemistry, histology, pathology, physiology, pharmacology, and psychology. Communication between scientists from these various disciplines-vital to the advancement of our understanding of the function of the nervous system-has become more and more difficult in recent years. Both increasing specialization and the incredible increases in publications pertinent to brain research in a wide spectrum of journals, in symposium volumes, in monographs, in abstracts, and in reviews contrib ute to the problems of cross-communication and even of communication within a scientific discipline. Research on the significance of cyclic nucleo tides to the function of nervous systems is particularly illustrative of the communication problem. Since the initial publications by Sutherland, Rall, and Butcher in the late fifties and early sixties on high levels of adenylate cyclase, phosphodiesterases, and cyclic AMP in brain, the ensuing litera ture of this field has expanded exponentially. At the present time, from five to ten publications relevant to cyclic nucleotides and the nervous system appear each week. Indeed, these are minimal numbers based mainly on examination of literature titles and key index words. Many articles concerned with some aspect of central function contain, buried within their text, experiments with or related to cyclic nucleotides.

The purpose of the present volume, the first of two on the pharmacology, biochemistry, and physiology of cyclic nucleotides, is to provide a comprehensive and up-to-date anthology on the nature and role of these important chemical regulators. Each of the chapters is the work of internationally known researchers who present a lucid and detailed review of their subject and not merely a single laboratory's viewpoint. The chapters emphasize critical assessments of the field rather than mere listings of experimental findings. By so doing, the contributors present the role of cyclic nucleotides in relationship to other intracellular regulators. Each chapter begins with a detailed summary to allow the reader to obtain a rapid overview of subsequent material. In addition, there are extensive bibliographies and a detailed subject index. Wherever pertinent, the chapters contain sections on drug mechanisms, physiological relevance, and disease processes. The Volume is divided into two sections, each beginning with an overview written by Professors T. W. RALL and P. GREENGARD, respectively. The first section focuses on the detailed pharmacology and chemistry of cyclic nucleotides, including their formation, degradation, measurement, and interaction with various modulatory agents, such as receptors and calcium. The second section is concerned with the biochemistry of protein phosphorylation, a process which appears to be one of the most important mechanisms for the intracellular expression of cyclic nucleotide action in eukaryotic cells.

Cyclic nucleotides are intimately involved in the consequences of either stimulation or blockade of receptors; therefore, an understanding of the biochemistry of cyclic nucleotides ought to be important for pharmacologists. Pharmacology is a science that among other things investigates chemical compounds that affect the physiology of cells, tissues and organs. Frequently pharmacologists account for the effect of low concentrations of a drug upon a tissue by invoking the presence of a receptor upon the surface of the cell. Traditional pharmacologists excelled at identifying and classifying the properties of receptors. A. J. CLARK'S monograph in the earlier series of the Handbook of Experimental Pharmacology (CLARK 1937) summarized the mathematics underlying the traditional pharmacological approach towards receptors. By its nature, however, classic pharmacology provided little useful information about the intracellular events occurring as a consequence of occupying a receptor; for example, ALQUIST (1948) identified the beta-adrenocep tor, but he did not provide any insight into how stimulation of the receptor produces tissue-specific physiological responses. The discovery of cyclic AMP by RALL and SUTHERLAND (see RALL, Vol. I) led to biochemical investigations of many different receptors (including ALQUIST'S beta-adrenoceptor) that share a cyclic nucleotide as a common factor in the biochemical mechanisms that translate the occupancy of receptors into physiological effects. Ten years ago, in the introduction to their monograph on cyclic nucleotides, ROBISON et al. (1971) commented on the rapid growth of interest in cyclic nucleotides over the preceding years.

This valuable resource provides a systematic account of the biochemistry of smooth muscle contraction. As a comprehensive guide to this rapidly growing area of research, it covers the structure and characteristic properties of contractile and regulatory proteins, with special emphasis on their predicted function in the live muscle. Also included in this book are intermediate filament proteins, and desmin and vimentin, whose function in smooth muscle is unknown; and several enzymes involved in the phosphorylation-dephosphorylation of contractile and other proteins.