RP4: Synaptic regulation of GABAA receptor turnover

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GABAA receptors (GABAARs) undergo extensive endocytosis in neurons followed by either recycling to the surface membrane or protein degradation. Clathrin-dependent endocytosis appears to be the major mechanism that initiates receptor internalization. The clathrin-adaptor protein 2 (AP2) associates with GABAARs via the μ2 subunit. PKA as well as PKC-dependent phosphorylation regulate the surface stability of GABAARs. Different GABAAR binding proteins participate in the regulation of internalized receptor fate. For instance, the Huntingtin-associated protein (HAP1) binds to GABAAR β subunits and HAP1 overexpression inhibits GABAAR degradation, thereby increasing receptor recycling. Similarly, Plic-1 appears to regulate receptor turnover and facilitates GABAAR accumulation at neuronal surface membranes.In the first FG885 funding period, our results added a new player to the system controlling synaptic GABAAR turnover. The ubiquitin-specific protease Usp14 appears to regulate α1 subunit-containing GABAARs that carry a mono-/oligo-ubiquitin label. Genetic knockdown of Usp14 generates an ataxia phenotype, represented by an extensive GABAAR redistribution to the neuron surface. These effects are reversible and require the catalytic protease activity of Usp14 enzymes.Recent data from our laboratory identified two actin-based myosin motor proteins that associate with al subunit-containing GABAARs. The nature of myoV, representing an anterograde motor, as well as the nature of myoVI moving in retrograde directions, suggests that both factors might be the drivers that mediate GABAAR redistribution between plasma membrane and submembrane vesicle compartments. In analogy to the turnover of AMPA-type glutamate receptors, the proposed project aims to study the mechanisms of GABAAR-myosin interactions. Due to the nature of inhibitory synapses that mainly locate at dendrite shafts, rather than at the regionally restricted spine head compartments, we expect to identify principal mechanisms of neurotransmitter receptor turnover that differ from turnover mechanisms at excitatory synapses.