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Research has been conducted on the dopamine D1-like receptors. Experimental results demonstrate that these receptors modulate N-methyl-D-aspartate glutamate receptor-mediated functions via direct protein-protein interactions.

Author(s): Fang Liu [1, 2, 3]; Qi Wan [4]; Zdenek B. Pristupa [1, 2]; Xian-Min Yu [1, 2, 6]; Yu Tian Wang [4]; Hyman B. Niznik (corresponding author) [1, 2, [...]

The N-methyl-D-aspartate (NMDA) receptor is a principal subtype of glutamate receptor mediating fast excitatory transmission at synapses in the dorsal horn of the spinal cord and other regions of the central nervous system. NMDA receptors are crucial for the lasting enhancement of synaptic transmission that occurs both physiologically and in pathological conditions such as chronic pain. Over the past several years, evidence has accumulated indicating that the activity of NMDA receptors is regulated by the protein tyrosine kinase, Src. Recently it has been discovered that, by means of up-regulating NMDA receptor function, activation of Src mediates the induction of the lasting enhancement of excitatory transmission known as long-term potentiation in the CA1 region of the hippocampus. Also, Src has been found to amplify the up-regulation of NMDA receptor function that is produced by raising the intracellular concentration of sodium. Sodium concentration increases in neuronal dendrites during high levels of firing activity, which is precisely when Src becomes activated. Therefore, we propose that the boost in NMDA receptor function produced by the coincidence of activating Src and raising intracellular sodium may be important in physiological and pathophysiological enhancement of excitatory transmission in the dorsal horn of the spinal cord and elsewhere in the central nervous system.

Na+ influx is essential for basic signals such as action potentials and excitatory postsynaptic potentials. Intracellular Na+ ((Na+)i) concentration increases in neuronal soma and dendrites during high levels of discharge activity or periods of bursting. It is shown that (Na+)i controls NMDA receptor functions. Increased (Na+)i led to increased NMDA-receptor-mediated whole-cell currents and NMDA-receptor single-channel activity.

The involvement of NMDA-type glutamate receptor in neuronal injury established in experimental stroke and neurotrauma models has been recently challenged by failures in treatment of stroke/neurotrauma patients with NMDA receptor antagonists. NMDA receptor activity is known to be essential for mediating a multitude of physiological functions. However, how NMDA receptors are recruited to cause neuronal injury remains unclear. Here we report that the time period during which initial NMDA receptor up-regulation occurs is critical for the recruitment of NMDA receptors causing neuronal injury during extracellular calcium (Ca2+) reperfusion in cultured hippocampal neurons, and represents the key period for neuronal protection by NMDA receptor antagonists. Furthermore, we identified that via intracellular sodium (Na+), extracellular Ca2+ depletion induces the up-regulation of NMDA receptor gating. Taken together, our study provides direct experimental evidence suggesting that determination of when and how NMDA receptors are recruited to cause neurotoxicity is essential for guiding treatment via antagonism of NMDA receptor functions. [ABSTRACT FROM AUTHOR]

Src kinase regulation of N-methyl-D-aspartate (NMDA) subtype glutamate receptors in the central nervous system (CNS) has been found to play an important role in processes related to learning and memory, ethanol sensitivity and epilepsy. However, little is known regarding the mechanisms underlying the regulation of Src family kinase activity in the control of NMDA receptors. Here we report that the distal phosphatase domain (D2) of protein tyrosine phosphatase a (PTPα) binds to the PDZ2 domain of post-synaptic density 95 (PSD95). Thus, Src kinase, its activator (PTPα) and substrate (NMDA receptors) are linked by the same scaffold protein, PSD95. Removal of PTPα does not affect the association of Src with NMDA receptors, but turns off the constitutive regulation of NMDA receptors by the kinase. Further- more, we found that application of the PTPα catalytic domains (D1 + D2) into neurones enhances NMDA receptor-mediated synaptic responses. Conversely, the blockade of endogenous PTPα inhibits NMDA receptor activity and the induction of tong-term potentiation in hippocampal neurones. Thus, PTPα is a novel up-regulator of synaptic strength in the CNS. [ABSTRACT FROM AUTHOR]