Molecular Physiology of Glycine Receptors in Vertebrate Nervous Systems

Abstract

Glycine is the simplest amino acid in biological organisms. Apart from its main role -as a structural "brick" in protein macromolecules -glycine has another extremely important function, as a neurotransmitter operating in synapses in the nervous system. Studies in the 1960s and 1970s demonstrated that fast inhibitory synaptic transmission in vertebrate nervous systems is provided by two main systems: the GABAergic and the glycinergic. The neurotransmitter in the former is γ-aminobutyric acid (GABA), while the neurotransmitter in the latter is glycine. Ionotropic GABA receptors are present mainly in synapses in the brain, while glycine receptors dominate in the spinal cord and brainstem. These receptors are colocated in some areas of the nervous system [14,155,162]. Furthermore, GABA and glycine can be present in the same synaptic vesicle [162] and are released from presynaptic terminals simultaneously [79].The physiological functions of the glycinergic system are very diverse: from controlling motor activity and generating rhythms to processing sensory information. The main function is to transmit inhibitory spikes in the spinal cord, supporting the rapid regulation of motor activity [45]. The functioning of glycine receptors depends on their location in the nervous system, their subunit composition, their regulation by second messengers (protein kinases, phosphatases, calcium ions), and ion concentrations in the intracellular and extracellular spaces [100,106].This review will address the physiological functions of the glycine receptor family, their molecular organization, and impairments to the structures of these macromolecular complexes resulting in pathological sequelae.The fi rst evidence that glycine might play a role as an inhibitory neurotransmitter was obtained in the 1960s. Electrophysiological experiments using iontophoretic application of various compounds to spinal cord neurons demonstrated that glycine evoked decreases in the activity of these neurons [34]. Biochemical studies showed that the glycine concentrations in spinal cord tissues were much greater than those in other parts of the nervous system [4,5]. This suggested that glycine has a role as a major neurotransmitter in the spinal cord. Furthermore, studies identifi ed an antagonist Glycine receptors are anion-selective channels supporting rapid synaptic transmission in vertebrate central nervous systems. Along with acetylcholine, nicotine, GABA A , and serotonin (5-HT 3 R) receptors, glycine receptors are members of the cys-loop pentameric ligand-sensitive receptor family. One β and four α subunits have been cloned from various species. Because of their specifi c distribution and molecular functional features, they perform a variety of physiological functions -from controlling motor activity through regulating neuron differentiation to processing sensory information and modulating pain sensitivity. The aim of the present review was to assess the overall picture formed by many years of studies of glycine receptors, briefl y presenting the m...