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However, whether and where functional NMDA receptors are expressed in pulmonary artery has not been established.

Hpa to bar Activator#

We previously demonstrated that NMDA receptor activation is linked to tissue plasminogen activator (tPA)-mediated inhibition of pulmonary arterial contractility and induction of vascular permeability 13, 14.

Analogous to the effect on neurons, excessive activation of NMDA receptors in lung triggers acute nitric oxide-dependent injury 11, 12, suggesting NMDA receptor-mediated excitotoxicity exists outside the central nervous system. Activation of NMDA receptors on these cells leads to calcium release and airway contraction 10. Recent study identified pulmonary airway smooth muscle cells as one cell type expressing NMDA receptors in lung 10. NMDA receptor subunits are expressed in all lung regions including trachea 9. While the expression and function of NMDA receptors in the nervous system have been studied extensively, their presence in non-neuronal tissues, including lung, is largely unexplored 8. in disorders such as stroke, AlzheimerвЂ™s disease and HuntingtonвЂ™s disease 1, 2. Activation of NMDA receptors by glutamate and its co-agonists glycine or d-serine, acting at GluN2 and GluN1 subunits, respectively, triggers calcium influx, which mediates neurophysiological processes at low levels of activation, but causes neuropathological outcomes at high levels, e.g. NMDA receptors have higher permeability to calcium than to sodium and potassium, and greater sensitivity to extracellular magnesium blockade, thus requiring membrane depolarization to open with high probability 1, 7. The subunit composition of NMDA receptors is region specific and subject to developmental regulations that can modulate their sensitivity to stimulation by potential agonists and toxins 5, 6. Different combinations of GluN1 and GluN2 subunits endow NMDA receptors with distinct biophysical and pharmacological properties and association with intracellular signaling molecules 5. Classical NMDA receptors are hetero-tetramers composed of two obligatory GluN1 subunits along with two GluN2 (2AвЂ“D) subunits 1, 4.

Hyperactivity and hypofunction of NMDA receptors are implicated in the pathogenesis of neurological and psychiatric disorders, respectively 1, 2, 3. N-methyl- d-Aspartate (NMDA) receptors are a subtype of ionotropic glutamate receptors essential for synaptic plasticity and memory formation 1, 2. Our findings show HPASMCs express functional NMDA receptors in line with their effect on pulmonary vasoconstriction, and thereby suggest a novel therapeutic target for pharmacological modulations in settings associated with pulmonary vascular dysfunction. HPASMCs also express high levels of serine racemase and vesicular glutamate transporter 1, suggesting a potential source of endogenous agonists for NMDA receptor activation. These subunits localize on the surface of HPASMCs and form functional ion channels as evidenced by whole-cell patch-clamp electrophysiology and reduced phenylephrine-induced contractile responsiveness of human pulmonary artery by the NMDA receptor antagonist MK801 under hypoxic condition. In addition, GluN1 and GluN2 (AвЂ“D) subunit proteins are expressed by human pulmonary artery smooth muscle cells (HPASMCs) in vitro and in vivo. We demonstrate that both GluN1 and GluN2 subunit mRNAs are expressed in HPA.

In the present study, we examined the expression of NMDA receptor subunit mRNA and protein in human pulmonary artery (HPA) by quantitative polymerase chain reaction (PCR), immunohistochemistry and immunoblotting. However, their presence and function at extraneuronal sites is less well characterized. N-methyl- d-aspartate (NMDA) receptors are widely expressed in the central nervous system.