Clinical Aspects Of Cyclic Nucleotides

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.

The cyclic purine nucleotides 3’,5’-cAMP and 3’,5’-cGMP are well-established second messengers. cGMP has recently been covered in a volume of the Handbook of Experimental Pharmacology (volume 191). In addition to 3’,5’-cAMP and 3’,5’-cGMP, so-called non-canonical cyclic nucleotides exist. These comprise the cyclic pyrimidine nucleotides 3’,5’-cCMP and 3’,5’-cUMP, the purine nucleotide 3’,5’-cIMP, the 2’,3’-nucleoside monophosphates and cyclic dinucleotides. In this volume of the Handbook of Pharmacology, word-leading experts in the field summarize our current knowledge on these non-canonical cyclic nucleotides, discuss open questions, future research directions and the pharmacotherapeutic implications. Special emphasis will be given to the emerging roles of 3’,5’-cCMP and 3’,5’-cUMP as second messengers with regard to generators, effectors, biological functions, inactivation and bacterial toxins. The role of 3’,5’-cIMP as potential second messenger will also be critically discussed. Furthermore, we will consider transport of cyclic nucleotides and their potential role as first messengers. The role of the cyclic dinucleotide cGAMP in the immune system will covered, too. Lastly, the book will present important methodological aspects ranging from mass-spectrometric methods for cyclic nucleotide detection to the synthesis of nucleotide analogs as experimental tools and holistic methods for analysis of cyclic nucleotide effects.

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 inform

Since the last major compendium dedicated to cyclic nucleotide phosphodiesterases (PDEs) was published over 15 years ago, an enormous amount of progress has occurred in the field. There is great need for a centralized source for key information in this burgeoning and therapeutically important area of medical research. Cyclic Nucleotide Phosph

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.