Neurotransmitters and second messengers

Michael E. Newman and Bernard Lerer

'Classical' second messengers Transduction systems—G proteins Effector enzymes—adenylate cyclase

Further actions of second messengers—phosphorylation. cascades

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Conciusions—implications for psychiatry Chapter. References

Since the catecholamine and indoleamine hypotheses of depression and the dopamine hypothesis of schizophrenia were first proposed, the effect of psychotropic drugs on brain monoamines and their receptors has been a central focus of research in psychopharmacology and biological psychiatry. In fact, effects of psychopharmacological agents on brain monoamines were extensively studied long before these hypotheses were formulated and were cardinal tenets upon which the theories were based. As will be outlined in this chapter, there has since been an explosion of knowledge in this field. This has involved a shift in emphasis from the neurotransmitters themselves to the multitude of receptors upon which they act and to mechanisms distal to the receptor up to and including effects on target gene expression. The increasing complexity of the field places a far greater burden of understanding upon the contemporary psychiatrist than was demanded of his or her predecessors in the more simple heyday of a few neurotransmitters and a limited number of receptors. With complexity, however, comes a far richer array of possibilities to understand the mechanism of action of antidepressant, antipsychotic, and other psychotropic drugs and a vast number of potential targets for new drug development.

Neurotransmitters in the brain, like hormones in the periphery, are located extracellularly and exert their effects by binding to receptors situated on the outer surface of the cell membrane. Transmission of the message carried by the neurotransmitter beyond the cell membrane thus depends on activation by the receptor of a signalling system which is not limited by the physical constraints of the membrane. Neurotransmitter receptors in the central nervous system have been divided into two classes.(1) The first class, known as ionotropic receptors, are directly linked to ion channels and respond to activation by a neurotransmitter within a millisecond timeframe. Each receptor consists of an oligomeric transmembrane protein containing both the ion channel and the agonist binding site(s). The molecular mass of the oligomer is 200 to 250 kDa and is composed of subunits of about 50 kDa, each subunit containing four transmembrane segments. Examples of class I receptors are the nicotinic cholinergic receptor, the g-aminobutyric acid A ( GABAA) receptor, and the receptors for glycine and glutamate.

The second class, known as metabotropic receptors, mediate responses over a longer time frame, with a latency of onset of at least 30 ms, and in general serve to modulate the signals generated by the class I receptors. Class II receptors have a characteristic heptahelical structure with seven hydrophobic transmembrane domains linked by hydrophilic groups (Fig, 1).(2) Attached to the N-terminal end is a large extracellular loop which contains the ligand binding domain, while the

C-terminal end is cytoplasmic. These receptors are linked to effector units which are either ion channels or enzymes responsible for generating small molecules that in general are able to diffuse intracellularly. These small molecules were originally referred to as second messengers since they propagate the signal initially carried by the neurotransmitter or first messenger. It is now clear, however, that these molecules represent one step along a pathway of sequential events referred to as a signal transduction cascade. Furthermore, multiple interactions between signal cascades originally thought to be completely separate have now been documented. Although the term 'second messenger' will be retained in this chapter because of its historical importance, it should be clear that the general function of second-messenger molecules does not differ from that of other molecules that participate in the signalling cascade. A more correct terminology would therefore use the term 'intracellular messengers' for all these substances.

Fig. 1 The structure of a metabotropic (G-protein-coupled) receptor. The receptor illustrated is the human b 2-adrenergic receptor, but the structure is similar to that of the bradrenergic receptor, the muscarinic acetylcholine receptor and to rhodopsin. The receptor possesses seven hydrophobic regions which span the plasma membrane, thus creating extracellular as well as intracellular loops. The amino terminus is extracellular while the carboxyl terminal region is cytoplasmic. (Reproduced with permission from R.J. Lefkowitz, B.K. Kobilka, and M.G. Caron (1989). The new biology of drug receptors. Biochemical Pharmacology, 38, 2941-8.) Printed with permission from Elsevier Science.

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