Properties of vertebrate glutamate receptors: Calcium mobilization and desensitization

Abstract

Glutamate is now recognized as a major excitatory neurotransmitter in the vertebrate CNS, participating in a number of physiological and pathological processes. The importance of glutamate in the mobilization of intracellular Ca2+ as well as the relationship between excitatory and toxic properties has made it important to understand factors that regulate the responsivity of glutamate receptors. In recent years considerable insight has been gained about regulatory sites on NMDA receptors, with the recognition that these receptors are modulated by multiple endogenous and exogenous agents. Less is known about the regulation of responses mediated by AMPA, kainate, ACPD or APB receptors. Desensitization represents a potentially powerful means by which glutamate responses may be regulated. Indeed, two agents closely linked to the physiology of NMDA receptors, glycine and Ca2+, appear to modulate different types of desensitization. In the case of glycine, alteration of a rapid form of desensitization may be important in the role of this amino acid as a necessary cofactor for NMDA receptor activation. Additionally, changes in the affinity of the receptor complex for glycine may underlie the use-dependent decline in NMDA responses under certain conditions. Likewise, Ca2+ is a crucial player in the synaptic and toxic effects mediated by NMDA receptors, and is involved in a slower form of desensitization, in effect helping to regulate its own influx into neurons. The site and mechanism of the Ca2+ regulatory effects remain uncertain with evidence supporting both intracellular and ion channel sites of action. A clear role for Ca(2+)-dependent desensitization in the function of NMDA receptors under physiological conditions has not yet been demonstrated. AMPA receptor desensitization has been an area of intense investigation in recent years. The rapidity and degree of this process, coupled with its apparent rapid recovery, has suggested that desensitization is a key mechanism for the short-term regulation of responses mediated by these receptors. Furthermore, rapid desensitization appears to be one factor determining the time course and efficacy of fast excitatory synaptic transmission mediated by AMPA receptors, highlighting the physiological relevance of the process. The molecular mechanisms underlying desensitization remain uncertain. Traditionally, desensitization, like inactivation of voltage-gated channels, has been thought to represent a conformational change in the ion channel complex (Ochoa et al., 1989). However, it is unknown to what extent desensitization, in particular rapid AMPA receptor desensitization, has mechanistic features in common with inactivation. In voltage-gated channels, conformational changes in the channel protein restrict ion flow through the channel (Stuhmer, 1991).(ABSTRACT TRUNCATED AT 400 WORDS)