Purinergic Receptors in the Nervous System

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This chapter focuses on the localization and roles of purinergic receptor subtypes in the central nervous system (CNS), as comprehensive reviews of purinergic signaling in the peripheral nervous system. The concept of purinergic neurotransmission is the existence of postjunctional purinergic receptors. A basis for distinguishing two types of purinoceptor, identified as P1 and P2 [for adenosine and adenosine triphosphate (ATP)/adenosine diphosphate (ADP), respectively], was proposed by Burnstock in 1978, but it was not until 1985 that a basis for distinguishing two types of P2 receptor(P2X and P2Y) was suggested, largely on the basis of pharmacological criteria. Pamela Holton provided the first hint of a transmitter role for adenosine triphosphate (ATP) in the nervous system by demonstrating the release of ATP during antidromic stimulation of sensory nerves . Then, in 1970, it was proposed that nonadrenergic, noncholinergic (NANC) nerves supplying smooth muscle of the gut and bladder utilized ATP as a neurotransmitter. The experimental evidence included the mimicry of the NANC nerve-mediated response by ATP; the measurement of the release of ATP during the stimulation of NANC nerves with luciferin-luciferase luminometry; histochemical labeling of the subpopulations of neurons in the gut and the bladder with quinacrine—a fluorescent dye known to selectively label high levels of ATP bound to peptides; and the demonstration that the slowly degradable analogue of ATP—αβ-methylene ATP, which produces selective desensitization of the ATP receptor—blocks the responses to NANC nerve stimulation.

Introduction

Pamela Holton provided the first hint of a transmitter role for adenosine triphosphate (ATP) in the nervous system by demonstrating release of ATP during antidromic stimulation of sensory nerves (Holton, 1959). Then, in my laboratory in Melbourne in 1970, we proposed that nonadrenergic, noncholinergic (NANC) nerves supplying smooth muscle of the gut and bladder utilized ATP as a neurotransmitter (Burnstock 1970, Burnstock 1972). The experimental evidence included mimicry of the NANC nerve-mediated response by ATP; measurement of release of ATP during stimulation of NANC nerves with luciferin-luciferase luminometry; histochemical labeling ofsubpopulations of neurons in the gut and the bladder with quinacrine, a fluorescent dye known to selectively label high levels of ATP bound to peptides; and the demonstration that the slowly degradable analogue ofATP, αβ-methylene ATP, which produces selective desensitization of the ATP receptor, blocks the responses to NANC nerve stimulation. The term “purinergic” and the evidence for purinergic transmission in a wide variety of systems were presented in an early pharmacological review (Burnstock, 1972).

Implicit in the concept of purinergic neurotransmission is the existence of postjunctional purinergic receptors. A basis for distinguishing two types of purinoceptor, identified as P1 and P2 [for adenosine and ATP⧸adenosine diphosphate (ADP), respectively], was proposed (Burnstock, 1978), but it was not until 1985 that a basis for distinguishing two types ofP2 receptor (P2X and P2Y) was suggested, largely on the basis of pharmacological criteria. Further P2 receptor subtypes followed including a P2T receptor selective for ADP on platelets and a P2Z receptor on macrophages (Gordon, 1986), and a P2U receptor that could recognize pyrimidines such as uridine triphosphate (UTP) as well as ATP (O'Connor et al., 1991). Abbracchio and Burnstock (1994), on the basis of studies of transduction mechanisms (Dubyak, 1991) and the cloning of P2Y (Lustig 1993, Webb 1993) and later P2X purinoceptors (Brake 1994, Valera 1994), proposed that purinoceptors should be considered to belong to two major families: a P2X family of ligand-gated ion channel receptors and a P2Y family of G-protein-coupled purinoceptors. This nomenclature has been widely adopted and currently seven P2X subtypes and about eight P2Y receptor subtypes are recognized (Burnstock, 2001) (Table I). The current consensus is that three P2X subtypes combine either as homomultimers or heteromultimers to form ion pores and there is growing recognition that heterodimers might form between P2Y receptor subtypes (see Chapter 1 of this volume (Burnstock, ATP and its metabolites as potent extracellular agonists)). In addition hetero-oligomerization of adenosine A1 receptors with P2Y1 receptors in rat brain has been proposed (Yoshioka et al., 2002).

Most studies of fast signaling in the nervous system have been concerned with the role of ATP acting postjunctionally as a transmitter orcontransmitter (see Burnstock 1976, Burnstock 1990a, Burnstock 1990b), whereas adenosine, after ectoenzymatic breakdown of released ATP, acts largely as a prejunctional modulator of transmitter release (see Dunwiddie 1985, Ribeiro 1995). In addition, there are many examples of the potent long-term (trophic) effects of ATP, UTP, and related compounds on neurons and glial cells (see Neary et al., 1996) and on peripheral nerve, smooth muscle, and epithelial cell proliferation, growth, and differentiation (Fig. 1) (see Abbracchio and Burnstock, 1998).

In this chapter, I will focus on the localization and roles of P2 receptor subtypes in the central nervous system (CNS), as comprehensive reviews of purinergic signaling in the peripheral nervous system have been published recently (Burnstock 1996, Burnstock 1999a, Burnstock 2000, Burnstock 2001b, Burnstock 2001c, Ralevic 1998, Burnstock 1997, Williams 1997, Kennedy 2001, Dunn 2001, King 2000), although reviews on limited aspects of purinergic signaling in the CNS are available (Burnstock 1977, Phillis 1981, Inoue 1996, Dunwiddie 1996, Gibb 1996, Abbracchio 1997, Robertson 1998); the recent reviews by Nörenberg and Illes (2000) and by Masino and Dunwiddie (2001) are particularly useful. The recent volume of Progress in Brain Research edited by Illes and Zimmermann also contains valuable articles on both the peripheral and central nervous systems (Illes and Zimmermann, 1999).

Section snippets

Sympathetic Nerves

The first hint about sympathetic purinergic cotransmission was in a paper published by Burnstock and Holman, 1962, in which they recorded excitatory junction potentials (EJPs) in smooth muscle cells of the vas deferens in response to stimulation of the hypogastric nerves. Although these junction potentials were blocked by guanethidine, which prevents the release of sympathetic neurotransmitters, we were surprised at the time that adrenoceptor antagonists were ineffective (Burnstock and Holman,

Sensory and Autonomic Ganglia

An effect of ATP on autonomic ganglia was first reported in 1948 when Feldberg and Hebb demonstrated that intraarterial injection of ATP excited neurons in the cat superior cervical ganglion (SCG) (Feldberg and Hebb, 1948). Later work from deGroat's laboratory showed that in the cat vesical parasympathetic ganglia and rat SCG, purines inhibited synaptic transmission through P1 receptors, but high doses of ATP depolarized and excited the postganglionic neurons (Theobald and de Groat, 1977,

Future Developments

The field of nucleotides and their receptors in the nervous system is still in its infancy and I predict a rapid expansion of interest in this field in the coming years. Some of the directions these studies are likely to take are the development of transgenic mice with absent or enhanced P2 receptor subtypes, behavioral studies of the effects of purines and pyrimidines and related compounds applied to the brain, trophic roles of nucleotides in cell development and death in various

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