LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES The Role of Cyclic Nucleotides in the CNS JOHN W. PHILLIS Vol. 4, No. 3 AUGUST 1977- 151 Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.76, on 01 Oct 2021 at 16:09:35, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S031716710002521X THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES CONTENTS A. Introduction 153 (4) Histamine 161 (5) Adenosine 161 B. General Features of Chemical (6) Acetylcholine and Substance P 162 Transmission Between Nerve Cells ...154 (7) Amino Acids 162 I. Electrophysiology of Synaptic (8) Prostaglandins 162 Transmission 154 (1) Fast Synapses 154 E. Nucleotides and Transmission (2) Slow Synapses 155 at Selected Synapses 163 (3) Presynaptic Inhibition 156 I. Sympathetic Ganglia 163 II. Identification of Synaptic Transmitters ...156 II. Central "Aminergic" Transmission 165 (1) Norepinephrine-Mediated Synapses .... 165 C. Metabolism and Functional (a) Cerebellar Purkinje Cells Characteristics of Cyclic and Hippocampal Pyramidal Neurons 165 Nucleotides 157 (b) Cerebral Cortex 165 I. Components of the Cyclic Nucleotide (c) Spinal Motoneurons 166 System (2) Dopamine-Mediated Synapses 166 (1) Adenylate Cyclase 157 (3) Serotonin-Mediated Synapses 167 (2) Guanylate Cyclase 157 (4) Histamine-Mediated Synapses 167 (3) Protein Kinases 157 (4) Phosphodiesterase 158 III. Depressant Actions of Cyclic and Non- (5) Phosphoprotein Phosphatases 158 Cyclic Adenine Nucleotides 168 (1) Cerebellar Purkinje Cells 168 II. Criteria for Acceptance of Cyclic (2) Cerebral Cortical Neurons 170 Nucleotides as Second Messengers 158 (3) Other Regions of the Brain 173 (4) Spinal Cord 173 D. Formation of Cyclic IV. Presynaptic Actions of Cyclic AMP '74 Nucleotides in the CNS 159 V. Acetylcholine and Cyclic GMP 176 I. Preparations used for Studies on VI. Phosphodiesterase Inhibitors 177 Cyclic Nucleotides 159 VII. Prostaglandins 177 (1) Investigations in vivo 159 (2) Brain Slice Preparations 159 F. Amines, Calcium and Na+ , K+ (3) Cells from Neuronal or Glial Cultures 160 —ATPase 178 (4) Cell-free Preparations of Adenylate Cyclase 160 G. Cyclic Nucleotides and Memory 183 II. Neurotransmitters Affecting Cyclic Nucleotide Formation 160 H. Conclusions 184 (1) Norepinephrine 160 (2) Dopamine 161 I. Acknowledgements 185 (3) Serotonin 161 J. References 185 152 - AUGUST 1977 Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.76, on 01 Oct 2021 at 16:09:35, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S031716710002521X LE JOURNAL CANADIEN DES SCIENCES NEUROLOG1QUES The Role of Cyclic Nucleotides in the CNS JOHN W. PHILLIS SUMMARY: On the basis of the infor­ pense of new difficulties. Prior blockade A. INTRODUCTION mation presented in this review, it is dif­ of the adenosine receptor with agents Cyclic AMP (cAMP, adenosine ficult to reach any firm decision regard­ such as theophylline or adenine xylofura- 3', 5'-monophosphate) was initially ing the role of cyclic AMP (or cyclic noside may also assist in the categoriza­ GMP) in synaptic transmission in the tion of responses to extracellularly ap­ discovered by Sutherland and Rail brain. While it is clear that cyclic nucleo­ plied cyclic AMP as being a result either (1958) as a heat stable factor ac­ tide levels can be altered by the ex­ of activation of the adenosine receptor cumulated in liver homogenates ex­ posure of neural tissues to various neuro­ or of some other mechanism. Ultimately, posed to epinephrine or glucagon transmitters, it would be premature to the development of highly specific in­ which mediated the glycogenolytic claim that these nucleotides are, or are hibitors for adenylate cyclase should action of these hormones on the not, essential to the transmission pro­ provide a firm basis from which to liver. Further investigations have led cess in the pre- or postsynaptic compon­ draw conclusions about the role of cyclic to the concept that cyclic AMP may ents of the synapse. In future experi­ AMP in synaptic transmission. Similar be involved as an intracellular ments with cyclic AMP it will be neces­ considerations apply to the actions of mediator of the actions of other sary to consider more critically whether cyclic GMP and the role of its synthe­ hormones and of various putative the extracellularly applied nucleotide sizing enzyme, guanylale cyclase. merely provides a source of adenosine synaptic transmitters. According to The use of phosphodiesterase in­ this concept, first messengers, the and is thus activating an extracellularly hibitors in studies on cyclic nucleo­ located adenosine receptor, or whether it hormones or transmitters them­ tides must also be approached with cau­ is actually reaching the hypothetical tion. The diverse actions of many of selves, travel from their cells of sites at which it might act as a second these compounds, which include calcium origin and induce the formation of messenger. The application of cyclic mobilization and block of adenosine up­ intracellular cyclic AMP in their AMP by intracellular injection techni­ take, could account for many of the re­ target cells. Cyclic AMP, by activat­ ques should minimize this particular ing an appropriate sequence of en­ problem, although possibly at the ex- sults that have been reported in the lit­ erature. zymes, can evoke the specific re­ sponse of a target cell to the hor­ mone (Sutherland et al., 1968). RESUME: En se basant sur Vinforma­ ment une source d'adenosine et active tion donnee dans cette revue, il est ainsi un receptuer d'adenosine localise Examples of systems in which difficile d'en arriver a une decision extracellulairement, ou si il rejoint en cyclic AMP is thought to function in ferme en ce qui concerne le role de fait les sites hypotheliques qui peuvent a second messenger capacity include VAMP cyclique (ou GMP cyclique) dans agir comme second messager. Lappli­ the liver, where as noted above cyc­ la transmission synaptique dans le cer- cation d AMP cyclique par techniques lic AMP mediates the actions of veau. Tandis qu'il est clair que les d'injection intracellulaire doivent mini- epinephrine and glucagon by mod­ niveaux de nucleotide cyclique peuvent miser ce probleme particulier, quoique ulating carbohydrate metabolism, i'tre modifies par Vexposition des tissus possiblement au coiit de nouvelles diffi- stimulating glycogen breakdown and nerveux a divers neurotransmetteurs, il cultes. Un bloc prealable du recepteur serail premature de pretendre que ces d'adenosine avec des agents comme la promoting the formation of glucose nucleotides sont, ou ne sont pas, essen- theophylline ou I'adenine xylofuranoside from metabolites such as amino tiels au processus de transmission dans peut aussi aider dans la classification acids and lactate. In pancreatic cells, les composantes pre- our post-synap- des reponses a I'AMP cyclique appli- it stimulates the secretion of insulin tiques de la synapse. Dans les experi­ quee extracellulairement, comme etant in response to glucagon and possibly ences futures avec I AMP cyclique, il un re suit at soit d'activation du recepteur to glucose. In fat cells it mediates the sera necessaire de considerer de facon dadenosine ou d'autres mecanismes. actions of hormones such as epine­ plus critique se le nucleotide applique Finalement, le developpement d'inhibi- phrine and glucagon which stimulate extracellulairement procure simple- (Continued on page 185) lipolysis and inhibit lipogenesis. Similar processes involving cyclic From the Department of Physiology, College of AMP are thought to govern other Medicine, University of Saskatchewan, Saskatoon, types of secretory cells. For exam­ Saskatchewan. ple, the actions of many trophic Reprint requests to Prof. J. W. Phillis, Dept. of hormones (ACTH, TSH, FSH) may Physiology, College of Medicine, University of be mediated through cyclic AMP. In Saskatchewan, Saskatoon, Saskatchewan, Canada. S7N 0W0. kidney tubule cells, cAMP stimu- Vol. 4, No. 3 AUGUST 1977- 153 Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.76, on 01 Oct 2021 at 16:09:35, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S031716710002521X THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES lates the reabsorption of water in an increasing awareness of the exis­ cyclic nucleotide function, such as response to antidiuretic hormone; in tence of extracellular adenosine re­ the generation of neuronal memory the myocardium it enhances the rate ceptors on nerve cells. Activation of traces at the single cell level, will be and force of cardiac contraction in these receptors must therefore be introduced. response to epinephrine; and in the considered as a possible complica­ bones it mediates the action of tion when cAMP is administered ex- parathyroid hormone in stimulating tracellularly — the route adopted by B. GENERAL FEATURES OF bone resorption and thus regulates most investigators. CHEMICAL TRANSMISSION the levels of serum calcium. Cyclic The present chapter will examine BETWEEN NERVE CELLS AMP has also been implicated in current knowledge of the role of Before proceeding to a description many of the processes of cell regula­ cyclic nucleotides in synaptic trans­ of the components of the cyclic nuc­ tion in which hormones may not be mission in the central nervous sys­ leotide system in the central nervous directly involved. tem. In particular,