Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • There are additional implications of subunit alterations in

    2021-11-25

    There are additional implications of α2-subunit alterations in the hippocampus. P has anticonvulsant activity (Herzog, 1995, Herzog et al., 1997, Herzog et al., 2012, Reddy et al., 2001, Reddy, 2010). These actions result from the metabolic conversion of P to GABA-A receptor-modulating, antiseizure neurosteroids (Frye et al., 2002, Reddy et al., 2004). During the menstrual cycle, circulating P levels are low in the follicular phase, but rise in the mid-luteal phase before declining around the premenstrual phase. Circulating AP levels increase in parallel to those of its parent P (Tuveri et al., 2008). Neurosteroid exposure and withdrawal, a disease model for perimenstrual catamenial epilepsy, has profound influence on GABA-A receptor subunit plasticity (Reddy, 2016). In the present study, we found that there is a sustained rise in α2-subunit expression during neurosteroid exposure with P treatment. This phenomenon is similar as in the diestrous phase with increased P level. This type of increased expression of α2 subunit with P treatment for 2 and 7days was also observed in NTERA-2 neuronal cells (Pierson et al., 2005). We utilized two distinct models to simulate the hormonal milieu of the luteal phase: natural estrous cycle and exogenous P administration. In both models, our results are consistent with a critical mediating role for neurosteroids in α2 mRNA expression. We didn’t utilize approaches to block natural P cycling because it may not reflect the local synthesis or accumulation of neurosteroids within the Fruquintinib australia (Reddy, 2010). In contrast to α4-subunit plasticity, the expression of α2-subunit remains unaffected with neurosteroid withdrawal. These findings are consistent with a previous report of increased α2 expression after pregnancy in rats (Brussaard et al., 1999). Neurosteroid withdrawal-related regulation of α4-subunit expression has been extensively studied in cerebellar granule cells (Follesa et al., 2000) and hippocampus neurons (Smith et al., 1998a, Gangisetty and Reddy, 2010, Wu et al., 2013). The potential role of neurosteroids in regulating α2-subunit expression is not well understood. P-related upregulation of α2-subunit was retained in PRKO mice (Fig. 2), suggesting that PRs are not responsible for the P regulation of α2-subunit expression. These findings are consistent with other GABA-A receptor subunits, specifically the PR-independent changes in α4 and δ-subunit expression following neurosteroid withdrawal (Gangisetty and Reddy, 2010, Wu et al., 2013) and ovarian cycle (Maguire and Mody, 2007). Nevertheless, based on the outcomes from finasteride experiments, we conclude that the regulation of α2-subunit plasticity is neurosteroid-dependent.
    Conclusions
    Materials and methods
    Conflicts of interest
    Acknowledgements This work was supported by the United States National Institutes of Health, National Institute of Neurological Disorders and Stroke Grant R01 NS051398 (to D.S.R.).
    Introduction γ-Amino butyric acid (GABA), in the mammalian central nervous system (CNS), exerts fast synaptic inhibition via actions on two distinct receptor subtypes: GABA-A and GABA-C rho (ρ) receptors. They are both Cl− permeable ionotropic receptors, but differ in biophysical, pharmacological and physiological properties [11]. The GABA-A receptor is a hetero-oligomeric and pentameric assembly of α1–α6, β1–β3, γ1–γ3, δ, ϵ, θ and π, subunits [22], whereas, GABA-C receptors are mainly a homo-, hetero- or hetero-oligo -meric assembly of ρ1-ρ3, subunits [14]. GABA-A and GABA-C receptors can also co-assemble as a functional receptor [24]. GABA-C receptors, are activated by cis- and trans- enantiomers, of GABA analogue 4-aminocrotonic acid, CACA and TACA [16], blocked competitively by (1,2,5,6-tetrahydropyridine-4-yl) methylphosphinic acid, TPMPA [28], and modulated by Fruquintinib australia divalent cations [3], [7], [17]. They are insensitive to GABA-A receptor antagonist bicuculline, allosteric modulators, such as, benzodiazepines and barbiturates [39], and only weakly modulated by neuroactive steroids [23].