Premium
Understanding the regulation of AMPA and NMDA iGluRs through the binding of sulfated neurosteroids
Author(s) -
Bartle Emily Irene,
Fanelli David,
Roark Ryan,
Young Amber,
Gentile Lisa
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.613.4
Subject(s) - ampa receptor , kainate receptor , pregnenolone sulfate , nmda receptor , chemistry , ionotropic effect , neuroscience , glutamate receptor , neuroactive steroid , silent synapse , long term depression , synaptic plasticity , ion channel linked receptors , receptor , biochemistry , microbiology and biotechnology , gabaa receptor , biology
AMPA, NMDA, and kainate receptors belong to the ionotropic glutamate (iGluR) family of receptors located in the post‐synaptic neural membrane. Upon binding to glutamate, a major fast excitatory neurotransmitter, these channels activate and play an important role in synaptic plasticity, learning and memory. Mis‐regulation of these receptors has been linked to neurodegenerative diseases such as Alzheimer's and Parkinson's. Our research is aimed at understanding the regulation of AMPA and NMDA receptors by the endogenous neurosteroids pregnenolone sulfate (PS) and 3α‐hydroxy‐5β‐pregnan‐20‐one sulfate (Pregas) for potential disease state applications. PS potentiates NMDA receptors containing NR2A or NR2B subunits, while inhibiting NMDA receptors containing NR2C or NR2D subunits and all other iGluRs. Likewise, Pregas negatively regulates all iGluRs. Our findings show that both neurosteroids bind to the amino terminal domain (ATD) and S1S2 domain of the NMDA NR2B and AMPA GluR2 subunits, but only bind to the ATD of the NDMA NR2D subunit. Intrinsic fluorescence studies confirm the binding of PS and Pregas to the subunit domains. Data from additional studies, including KD and Stern‐Volmer analysis, will be presented to further elucidate and differentiate binding.