Activation of membrane progesterone receptors mediates the metabotropic effects of neurosteroids on GABAAR phosphorylation and tonic inhibition
Neurosteroids have been well characterized as positive allosteric modulators of the
GABAAR. However, previous studies in our lab have identified an additional role for
neurosteroids in mediating phosphorylation and stability of α4-containing GABAARs.
In this body of work, I show through both biochemical and electrophysiological methods
that this novel role is (1) not specific to the... read moreα4 subunit; neurosteroids also
mediate phosphorylation of the β3 subunit and (2) this mechanism is independent of
the allosteric modulation, and instead functions through activation of membrane
progesterone receptors (mPRs). I demonstrate that pregnane steroids such as
allopregnanolone (3α,5α-THP), mediate phosphorylation of serines 383, 408
and 409 of the β3 subunit in the hippocampus. Allopregnanolone mediated
phosphorylation of these residues is through activation of both PKC and PKA signaling
mechanisms and results in enhanced tonic inhibition within the hippocampus.
Allopregnanolone has previously been shown to bind membrane progesterone receptor alpha
(mPRα) and activate downstream kinase signaling. To test the hypothesis that
neurosteroid mediated GABAAR phosphorylation is via activation of mPRs, I use both
progesterone (mPR agonist) and ORG OD 02-0 (synthetic agonist) to demonstrate an
enhancement of β3 phosphorylation and of tonic current. Additionally, I show these
effects are both blocked by PKC and PKA kinase inhibition. Finally, to elucidate a
specific mPR subtype responsible for mediating these effects, I demonstrate that
activation of mPRα significantly enhances β3 phosphorylation and
β3-containing GABAARs at the plasma
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Neuroscience.
Advisors: Stephen Moss, and Paul Davies.
Committee: Thomas Biederer, Jamie Maguire, Leon Reijmers, and Leslie Henderson.
Keyword: Nanoscience.read less