IBN 98-10505 PREMKUMAR The N-Methyl-D-Aspartate receptor (NMDAR) is a subtype of a class of proteins found in the cell membranes of neurons (nerve cells) termed "ionotropic excitatory amino acid receptors." These molecules are involved in detecting the presence of the amino acid glutamate, in the medium bathing a nerve cell and signaling the concentration of that amino acid by opening a pores in the membrane that admit especially calcium ions to the inside of the cell. In particular, this receptor type plays a central role in development, neuroplasticity (changes in the properties of the nervous system, as in learning) and excitotoxicity (cell-death due to over-stimulation). Important properties of the NMDAR, when compared to other channels are that it is highly permeable to Ca2+ and is blocked by Mg2+ in a voltage-dependent manner. The amount of Ca2+ entry is critical for the activation of Ca2+-dependent enzymes which produces second messengers (other chemicals which serve as signals to other parts of the cell), mediates cell death, and leads to an increase or decrease in synaptic strength. NMDAR is a potential target for modulation by second messengers, phosphorylation, and other physiological/pharmacological agents. The long-term goal of this project is to determine the modulation of Ca2+ permeability and Mg2+ block characteristics of NMDA receptors. Since the cloning of the first NMDAR subunit (NR1), eight different splice variants of NR1 subunit, four different NR2 (A-D), and an NMDA-like (NR-L, renamed as NR3) subunits have been cloned. NMDA receptors formed by different subunit combinations exhibit unique functional properties and play a critical role during development. In spite of these significant advances, the reason for the regional distribution and developmental regulation of receptors formed with different subunit combinations is not fully understood. The functional properties of these receptors are also not clearly understood. In this st udy Dr. Premkumar will determine Ca2+ permeability and Mg2+ block characteristics of NMDAR formed with different subunit combinations. Identification of subunit specific properties will reveal the need for these receptors to be expressed in a specific time-window during development. Results from this study will give us a better understanding of subunit-specific properties and provide insight into regional specificity of CNS function. This knowledge will also aid us to understand disease conditions and design novel drugs that can target specific brain regions. It has been clearly shown that stroke patients, who have been treated with NMDA receptor antagonist can recover faster compared to those who have not received the antagonist. It is suggested that the excess Ca2+ entry through NMDA receptors causes neuronal damage leading to slow recovery, sometimes the damage is irreversible.
