Molecular Mechanism of AMPA Receptor Modulation by TARP/Stargazin

Anat Ben-Yaacov, Moshe Gillor, Tomer Haham, Alon Parsai, Mohammad Qneibi, Yael Stern-Bach

نتاج البحث: نشر في مجلةمقالةمراجعة النظراء

ملخص

AMPA receptors (AMPARs) mediate the majority of fast excitatory transmission in the brain and critically contribute to synaptic plasticity and pathology. AMPAR trafficking and gating are tightly controlled by auxiliary transmembrane AMPAR regulatory proteins (TARPs). Here, using systematic domain swaps with the TARP-insensitive kainate receptor GluK2, we show that AMPAR interaction with the prototypical TARP stargazin/γ2 primarily involves the AMPAR membrane domains M1 and M4 of neighboring subunits, initiated or stabilized by the AMPAR C-tail, and that these interactions are sufficient to enable full receptor modulation. Moreover, employing TARP chimeras disclosed a key role in this process also for the TARP transmembrane domains TM3 and TM4 and extracellular loop 2. Mechanistically, our data support a two-step action in which binding of TARP to the AMPAR membrane domains destabilizes the channel closed state, thereby enabling an efficient opening upon agonist binding, which then stabilizes the open state via subsequent interactions.

اللغة الأصليةإنجليزيّة أمريكيّة
الصفحات (من إلى)1126-1137.e4
دوريةNeuron
مستوى الصوت93
رقم الإصدار5
المعرِّفات الرقمية للأشياء
حالة النشرنُشِر - 8 مارس 2017

All Science Journal Classification (ASJC) codes

  • !!General Neuroscience

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