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Functional NMDA receptors in red blood cells and heart


Makhro, Asya Victorovna. Functional NMDA receptors in red blood cells and heart. 2014, University of Zurich, Faculty of Science.

Abstract

N-methyl D-aspartate (NMDA) receptor is a nonselective cation channel formed four out of seven known subunits capable of binding glutamate or glycine. These amino acids are the agonists of the NMDA receptors in the brain where this receptor is involved in neurotransmission and intracellular signaling. Recently NMDA receptor expression and function were shown in several non-neuronal tissues. NMDA receptors were found in human bone marrow in osteoclasts, osteoblasts and hematopoietic precursor lineages. Expression of several of the NMDA receptor subunits was reported in mammalian myocardial tissue, however, the NMDA receptor function in the heart was never investigated.
The aim of the present study was to characterize NMDA receptor expression and its physiological and pathophysiological roles in the heart, and in red blood cells (RBC) as well as in erythroid precursor cells (EPCs). We were the first to report the presence of NMDA receptors in RBCs of rats and humans and in human and rat EPCs. Subunit composition of the erythroid receptors varied depending on the differentiation stage in human EPCs and differed substantially from that in the brain with NR2D and NR3B were the dominating over the neuronal NR1 and NR2B common in neurons. Erythroid receptors could be activated by the NMDA and glutamate. Stimulation of the NMDA receptors in humans EPCs as well as in human and rat RBCs resulted in massive transient Ca2+ uptake. Plasma-born glutamate and glycine were sufficient to maintain basal receptor activity which was controlled by the plasma agonists levels and, most likely, other humoral factors. We have demonstrated that abnormally high numbers of receptor copies in RBCs of sickle cell disease patients translate into excessive permeability of RBC membranes for Ca2+. As calcium is a master regulator of various processes in
RBCs, its uptake upon stimulation of the erythroid NMDA receptors resulted in
the alterations of cytoskeletal structure and cell volume, modulation of oxidative state, intracellular pH, and RBC half-life in the circulation. In the EPCs NMDA receptors are required for survival of precursor cells, particular at the earlier differentiation stages.
Our motivation to investigate the expression and function of the NMDA receptors in the heart was based on the fact that elevation of the plasma levels of the agonist of these receptors, homocysteine, was reported to be associated with several heart diseases including heart failure. We have characterized expression of the NMDA receptor subunits in different parts of rat myocardium and elaborated on the relation between the subunit composition of cardiac NMDA receptors and their pharmacology using “brainless rat heart model” (isolated blood-perfused heart) and sarcolemmal membrane preparations. Similar to that in RBCs, subunit composition of cardiac NMDA receptors differed substantially from that in the brain and showed remarkable chamber-dependent heterogeneity with NR3A and NR2D dominating. Expression of the NR2B subunit was age-dependent and most likely associated with hypertrophic remodeling.
Expression of the subunits NR2A and 2C was restricted to atria. We found that
NMDA receptor agonists and antagonists regulated autonomous heart rate and rhythmicity. Myocardial repolarization and depolarization rate were prolonged by the NMDA receptor antagonists. Our data indicate that cardiac NMDA receptors are an attractive target for pharmacological interventions to treat arrhythmias and other cardiovascular disorders.

Abstract

N-methyl D-aspartate (NMDA) receptor is a nonselective cation channel formed four out of seven known subunits capable of binding glutamate or glycine. These amino acids are the agonists of the NMDA receptors in the brain where this receptor is involved in neurotransmission and intracellular signaling. Recently NMDA receptor expression and function were shown in several non-neuronal tissues. NMDA receptors were found in human bone marrow in osteoclasts, osteoblasts and hematopoietic precursor lineages. Expression of several of the NMDA receptor subunits was reported in mammalian myocardial tissue, however, the NMDA receptor function in the heart was never investigated.
The aim of the present study was to characterize NMDA receptor expression and its physiological and pathophysiological roles in the heart, and in red blood cells (RBC) as well as in erythroid precursor cells (EPCs). We were the first to report the presence of NMDA receptors in RBCs of rats and humans and in human and rat EPCs. Subunit composition of the erythroid receptors varied depending on the differentiation stage in human EPCs and differed substantially from that in the brain with NR2D and NR3B were the dominating over the neuronal NR1 and NR2B common in neurons. Erythroid receptors could be activated by the NMDA and glutamate. Stimulation of the NMDA receptors in humans EPCs as well as in human and rat RBCs resulted in massive transient Ca2+ uptake. Plasma-born glutamate and glycine were sufficient to maintain basal receptor activity which was controlled by the plasma agonists levels and, most likely, other humoral factors. We have demonstrated that abnormally high numbers of receptor copies in RBCs of sickle cell disease patients translate into excessive permeability of RBC membranes for Ca2+. As calcium is a master regulator of various processes in
RBCs, its uptake upon stimulation of the erythroid NMDA receptors resulted in
the alterations of cytoskeletal structure and cell volume, modulation of oxidative state, intracellular pH, and RBC half-life in the circulation. In the EPCs NMDA receptors are required for survival of precursor cells, particular at the earlier differentiation stages.
Our motivation to investigate the expression and function of the NMDA receptors in the heart was based on the fact that elevation of the plasma levels of the agonist of these receptors, homocysteine, was reported to be associated with several heart diseases including heart failure. We have characterized expression of the NMDA receptor subunits in different parts of rat myocardium and elaborated on the relation between the subunit composition of cardiac NMDA receptors and their pharmacology using “brainless rat heart model” (isolated blood-perfused heart) and sarcolemmal membrane preparations. Similar to that in RBCs, subunit composition of cardiac NMDA receptors differed substantially from that in the brain and showed remarkable chamber-dependent heterogeneity with NR3A and NR2D dominating. Expression of the NR2B subunit was age-dependent and most likely associated with hypertrophic remodeling.
Expression of the subunits NR2A and 2C was restricted to atria. We found that
NMDA receptor agonists and antagonists regulated autonomous heart rate and rhythmicity. Myocardial repolarization and depolarization rate were prolonged by the NMDA receptor antagonists. Our data indicate that cardiac NMDA receptors are an attractive target for pharmacological interventions to treat arrhythmias and other cardiovascular disorders.

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Additional indexing

Item Type:Dissertation
Referees:Gassmann M, Bogdanova A, Hengartner M O, Rohr S
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2014
Deposited On:15 Jan 2015 09:52
Last Modified:05 Apr 2016 18:48
Number of Pages:132

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