As reported previously in recombinant receptors, nimodipine inhib

As reported previously in recombinant receptors, nimodipine inhibited synaptic GABAA receptor currents only at high concentrations (>30 mu M), significantly greater than attained in vivo (1 MM) 45 min after a single antagonist injection. Thus, the effects of nimodipine were unlikely to be related

to direct effects on GABAA receptors. As with nimodipine injection, buffering intracellular free [Ca2+] with BAPTA similarly prevented the effects on GABAA receptor-mediated synaptic transmission, suggesting intracellular Ca2+ homeostasis is important to maintain GABAA receptor Mdivi1 clinical trial function. The findings further support a role for activation of L-type VGCCs, and perhaps other Ca2+-mediated signaling pathways, in the modulation of GABAA receptor synaptic function following chronic benzodiazepine administration, independent of modulation of the

allosteric interactions between benzodiazepine and GABA binding sites. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Glycoproteins of several viruses have the capacity to induce release of noninfectious, capsidless particulate structures containing only the viral glycoprotein. Such structures are often called subviral particles VE 821 (SVP). Foamy viruses (FVs), a special type of retroviruses with a replication strategy combining features of both orthoretroviruses and hepadnaviruses, express a glycoprotein (Env) which has the ability to induce SVP release. However, unlike human hepatitis B virus, prototype FV (PFV) naturally secretes only small amounts of SVPs, because ubiquitination of the Env protein seems to suppress the intrinsic capacity for induction of SVP release. In this study, we characterized the structural determinants influencing PFV SVP release, examined the role of specific Env ubiquitination sites in the regulation of this process,

and analyzed the requirement of the cellular vacuolar protein sorting (VPS) machinery for SVP egress. We observed that the cytoplasmic and membrane-spanning domains of both the leader peptide (LP) and the transmembrane (TM) subunit harbor essential as well as inhibitory domains. Furthermore, only ubiquitination at the most N-terminal lysine residues (K-14 and K-15) most in LP reduced cell surface expression and suppressed SVP release to wild-type levels. This suggests that interaction of Env with cellular components required for SVP release suppression is effective only when Env is ubiquitinated at these lysine residues but not at others. Finally, SVP release was sensitive to dominant-negative mutants of late components, but not early components, of the cellular VPS machinery. PFV therefore differs from hepatitis B virus in using the same cellular pathway for egress of both virions and SVPs.

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