Modulation of the N-methyl-D-aspartate receptor by polyamines: molecular pharmacology and mechanisms of action.

Introduction Glutamate is the major fast excitatory neurotransmitter in the vertebrate central nervous system. Glutamate receptors that are ligand-gated ion channels are classified on the basis of their sensitivity to the selective agonists N-methyl-11-aspartate (NMDA), a-arnino-3-hydroxy-S-methyl-4-isoxazoleproprionic acid (AMPA) and kainate. NMDA receptors play a key role in the generation of various forms of synaptic plasticity, including some types of associative long-term potentiation and long-term depression which may underlie learning and memory, and in defining neuronal architecture and synaptic connectivity, including experiencedependent synaptic modifications in the developing nervous system [ 1,2]. Excessive or abnormally prolonged activation of NMDA receptors has been implicated in a number of pathological states including ischaemic neuronal cell death, epilepsy and chronic neurodegenerative diseases [ 3,4]. The NMDA receptor contains an integral ion channel that gates Na+ and Calf and is blocked at resting membrane potentials by physiological concentrations of Mg2+. The Mgz+ block of the ion channel is voltage-dependent and is relieved during membrane depolarization, allowing activation of the receptor complex by NMDA or glutamate [1,2]. The receptor contains a number of distinct recognition sites for endogenous and exogenous ligands, including glutamate (or NMDA), glycine, M$+, Zn2+, polyamines and open-channel blockers such as phenylcyclidine and MK-80 1 [ 11. The receptor is also modulated by pH, redox reagents, arachidonic acid and some neurosteroids. There is an absolute requirement for glycine for the channel to be opened by NMDA or glutamate. Thus, glycine can be considered a ‘co-agonist’ at the NMDA receptor complex [S]. Effects of polyamines on the NMDA receptor were first reported from ligand binding studies in which spermine and spermidine (3-300 pM) were shown to increase the binding of radiolabelled channel blockers such as ”-labelled MK-80 1 to the NMDA receptor-channel complex [6-lo]. At high concentrations of spermine and spermidine,