ABSTRACT
ABSTRACT: Group I metabotropic glutamate receptors (group I mGluRs) have been implicated in several central nervous system diseases including chronic pain. It is known that activation of group I mGluRs results in the production of inositol triphosphate (IP3) and diacylglycerol that leads to activation of extracellular signal-regulated kinases (ERKs) and an increase in neuronal excitability, but how group I mGluRs mediate this process remains unclear. We previously reported that Orai1 is responsible for store-operated calcium entry and plays a key role in central sensitization. However, how Orai1 is activated under physiological conditions is unknown. Here, we tested the hypothesis that group I mGluRs recruit Orai1 as part of its downstream signaling pathway in dorsal horn neurons. We demonstrate that neurotransmitter glutamate induces STIM1 puncta formation, which is not mediated by N-Methyl-D-aspartate (NMDA) or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Glutamate-induced Ca2+ entry in the presence of NMDA or AMPA receptor antagonists is eliminated in Orai1-deficient neurons. Dihydroxyphenylglycine (DHPG) (an agonist of group I mGluRs)-induced Ca2+ entry is abolished by Orai1 deficiency, but not affected by knocking down of transient receptor potential cation channel 1 (TRPC1) or TRPC3. Dihydroxyphenylglycine-induced activation of ERKs and modulation of neuronal excitability are abolished in cultured Orai1-deficient neurons. Moreover, DHPG-induced nociceptive behavior is markedly reduced in Orai1-deficient mice. Our findings reveal previously unknown functional coupling between Orai1 and group I mGluRs and shed light on the mechanism underlying group I mGluRs-mediated neuronal plasticity.
Subject(s)
N-Methylaspartate , Receptors, Metabotropic Glutamate , Animals , Calcium/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Glutamic Acid/metabolism , Mice , N-Methylaspartate/metabolism , N-Methylaspartate/pharmacology , ORAI1 Protein/genetics , ORAI1 Protein/metabolism , Posterior Horn Cells/metabolism , Receptors, AMPA/metabolism , Receptors, Metabotropic Glutamate/metabolism , Signal TransductionABSTRACT
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is an invaluable rescue therapy for patients suffering from cardiopulmonary arrest, but it is not without its drawbacks. There are cases where patients recover their cardiac function, yet they fail to wean to mechanical conventional ventilation (MCV). The use of high-frequency percussive ventilation (HFPV) has been described in patients with acute respiratory failure (RF) who fail MCV. We describe our experience with five patients who underwent VA-ECMO for cardiopulmonary arrest who were successfully weaned from VA-ECMO with HFPV after failure to wean with MCV. Weaning trials of HFPV a day before decannulation or at the time of separation from VA-ECMO were conducted. Primary endpoint data collected include pre- and post-HFPV partial pressures of oxygen (PaO2) and PaO2/FIO2 (P/F) ratios measured at 2 and 24 hours after institution of HFPV. Additional periprocedural data points were collected including length of time on ECMO, hospital stay, and survival to discharge. Four of five patients were placed on VA-ECMO subsequent to percutaneous coronary intervention. One patient had cardiac arrest secondary to RF. Mean PaO2 (44 ± 15.9 mmHg vs. 354 ± 149 mmHg, p < .01) and mean P/F ratio (44 ± 15.9 vs. 354 ± 149, p < .01) increased dramatically at 2 hours after the initiation of HFPV. The improvement in mean PaO2 and P/F ratio was durable at 24 hours whether or not the patient was returned to MCV (n = 3) or remained on HFPV (n = 2) (44 ± 15.9 mmHg vs. 131 ± 68.7 mmHg, p = .036 and 44 ± 15.9 vs. 169 ± 69.9, p < .01, respectively). Survival to discharge was 80%. The data presented suggest that HFPV may be used as a strategy to shorten time on ECMO, thereby reducing the negative effects of the ECMO circuit and improving its cost efficacy.
