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Abstract

Synaptic transmission between neurons relies on the exact spatial
organization of postsynaptic transmitter receptors, which are
recruited and positioned by dedicated scaffolding and regulatory
proteins. At GABAergic synapses, the regulatory protein collybistin
(Cb, also known as ARHGEF9) interacts with small GTPases, cell
adhesion proteins and phosphoinositides to recruit the scaffolding
protein gephyrin and GABAA receptors to nascent synapses. We
dissected the interaction of Cb with the small Rho-like GTPase TC10
(also known as RhoQ) and phospholipids. Our data define a protein–
lipid interaction network that controls the clustering of gephyrin at
synapses. Within this network, TC10 and monophosphorylated
phosphoinositides, particulary phosphatidylinositol 3-phosphate
(PI3P), provide a coincidence detection platform that allows the
accumulation and activation of Cb in endomembranes. Upon
activation, TC10 induces a phospholipid affinity switch in Cb, which
allows Cb to specifically interact with phosphoinositide species
present at the plasma membrane. We propose that this GTPase-
based regulatory switch mechanism represents an important step in
the process of tethering of Cb-dependent scaffolds and receptors at
nascent postsynapses.