Three Ca2+ channel inhibitors in combination limit chronic secondary degeneration following neurotrauma
Donna L. SavigniRyan O’Hare DoigC. SzymanskiCarole A. BartlettIvan LozićNicole M. SmithMelinda Fitzgerald
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TARP [transmembrane AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor regulatory protein] γ-8 is an auxiliary subunit of AMPA receptors that is widely distributed in the hippocampus. It has been shown that TARP γ-8 promotes surface expression of AMPA receptors; however, how TARP γ-8 regulates the expression of AMPA receptors remains unclear. In the present study, we examined the effect of TARP glycosylation on AMPA receptor trafficking. We first showed that TARP γ-8 is an N-glycosylated protein, which contains two glycosylation sites, Asn53 and Asn56, and compared this with the glycosylation of TARP γ-2 and the AMPA receptor auxiliary protein CNIH-2 (cornichon homologue 2). We next examine the effect of TARP glycosylation on TARP trafficking and also on AMPA receptor surface expression. We find that TARP γ-8 glycosylation is critical for surface expression of both TARP γ-8 and GluA1 in heterologous cells and neurons. Specifically, knockdown of TARP γ-8 causes a decrease in both total and surface AMPA receptors. We find that the expression of unglycosylated TARP γ-8 in cultured neurons is unable to restore GluA1 expression fully. Furthermore, when the maturation of TARP γ-8 is impaired, a large pool of immature GluA1 is retained intracellularly. Taken together, our data reveal an important role for the maturation of TARP γ-8 in the trafficking and function of the AMPA receptor complex.
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Abstract Purinergic contractions of the detrusor are reduced by cAMP, but the underlying mechanisms are unclear. We examined the effects of BK and Kv7 channel modulators on purinergic contractions of the detrusor and tested if the inhibitory effects of activators of the cAMP effectors, PKA and EPAC, were reduced by blockade of BK or Kv7 channels. Purinergic contractions of the murine detrusor were induced by electric field stimulation (EFS) or application of the P2X receptor agonist α,β‐MeATP. EFS responses were inhibited by the L‐type Ca 2+ channel blocker nifedipine, but not by the SERCA inhibitor CPA or the SOCE blocker GSK7975A. The Kv7 channel opener retigabine and BK channel activator compound X inhibited purinergic responses, while blockade of Kv7 or BK channels with XE991 or iberiotoxin, respectively, augmented these responses. Application of the EPAC activator 007‐AM or PKA activator 6‐MB‐cAMP inhibited EFS responses. These effects were unaffected by iberiotoxin; however, XE991 reduced the effects of 007‐AM, but not 6‐MB‐cAMP. Kv7.5 was the only Kv7 transcript detected in isolated detrusor myocytes. These data suggest that purinergic contractions of the detrusor are regulated by BK and Kv7 channels and the latter may also play a role in EPAC‐dependent inhibition of this activity.
Iberiotoxin
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Abstract After more than 60 years of research, the only purinergic compound approved on the basis of its ability to interact with adenosine receptors is adenosine itself in an i.v. formulation for the treatment of cardiac arrythmias. Yet purinergic systems in both the CNS and periphery have been implicated in a wide variety of diseases. The key to exploring the potential of purinergic therapeutics lies in the selection of appropriate therapeutic targets and the development of novel and selective ligands.
Purinergic Signalling
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Purinergic Signalling
Human physiology
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Abstract α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPA‐R)‐mediated neurotoxicity was studied in relation to subunit expression and the presence of Ca 2+ ‐permeable receptor channels. AMPA‐mediated toxicity had two components: 1) a direct AMPA‐R‐mediated component, which was not due to Ca 2+ influx through voltage‐gated Ca 2+ channels, reversal of the Na + /Ca 2+ exchanger or release of calcium from dantrolene‐sensitive intracellular Ca 2+ stores, and 2) a minor, indirect component involving activation of NMDA receptor channels, because of glutamate release and removal of the Mg 2+ block of the NMDA receptor on AMPA‐R stimulation. The involvement of Ca 2+ influx through AMPA‐R was also examined. The number of neurons possessing Ca 2+ ‐permeable AMPA‐R increased during culture development, concurrently with an increasing susceptibility for AMPA‐induced toxicity during development. GluR2( R ) levels also increased during development, and channel blockers of Ca 2+ ‐permeable AMPA‐R lacking the GluR2( R ) subunit (spermine and philanthotoxin) failed to prevent neurotoxicity or increases in [Ca 2+ ] i . Thus, the direct AMPA‐R‐mediated toxicity may be explained by initiation of cell death by Ca 2+ fluxing through AMPA‐R containing GluR2( R ). The components of direct AMPA‐R‐mediated toxicity are proposed to be 1) toxicity mediated by GluR2( R )‐lacking AMPA‐R and 2) toxicity mediated by low‐Ca 2+ ‐permeability AMPA‐R containing GluR2( R ). J. Neurosci. Res. 65:267–277, 2001. © 2001 Wiley‐Liss, Inc.
Neurotoxicity
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Functional Diversity
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It was in 1972 that Burnstock laid the foundation of a new nerve type that he called ‘purinergic nerves’. In this article, he presented experimental data using five criteria to establish that adenosine triphosphate can be considered to be a neurotransmitter, including (1) the release of a purinergic molecule from terminal axons, (2) the structures of purinergic nerves, (3) the electrophysiological properties of purinergic transmission, (4) the pharmacology of adenyl compounds and purinergic transmission, and (5) the distribution and evolution of the purinergic nerves. However, in spite of convincing data, it took more than 20 years for the scientific community to accept this hypothesis. Since then, it has been recognized that the purinergic system is involved in multiple short-term actions such as cell proliferation and pain.
Purinergic Signalling
Neurosecretion
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