Regulation of Somatodendritic GABA_A Receptor Channels in Rat Hippocampal Neurons: Evidence for a Role of the Small GTPase Rac1

Abstract

The role of the cytoskeleton in the activity of GABA(A) receptors was investigated in cultured hippocampal neurons. Receptor currents were measured with the whole-cell patch-clamp technique during repetitive stimulation with 1 microm muscimol. After destruction of the microtubular system with nocodazol, muscimol-induced currents showed a rundown by 78%. A similar rundown was observed when actin fibers were destroyed with latrunculin B or C2 toxin of Clostridium botulinum. Because the small GTPases of the Rho family RhoA, Rac1, and Cdc42 are known to control the organization of actin fibers, we investigated their possible involvement. Inactivation of the GTPases with clostridial toxins, as well as intracellular application of recombinant Rho GTPases, indicated that active Rac1 was necessary for full GABA(A) receptor activity. Immunocytochemical labeling of the receptors showed that the disappearance of receptor clusters in the somatic membrane as induced by muscimol stimulation was enhanced by Rac1 inactivation. It is suggested that Rac1 participates in the regulation of GABA(A) receptor clustering and/or recycling.

Interaction of the Pacemaker Channel HCN1 with Filamin A

“…This result suggests that Ral A, filamin A, and HCN1 are strictly packed in a macromolecular complex. It is also interesting to note that monomeric G-proteins of the Rho family, of which Ral A is a member, are involved in the modulation of ionic channels such as N-methyl-D-aspartate and ␥-aminobutyric acid type A receptors (38,39). We found that the interaction between HCN1 and filamin A is conserved in in vivo conditions as shown by co-immunoprecipitation of the two proteins from bovine brain (Fig.…”

Activity-Dependent Movements of Postsynaptic Scaffolds at Inhibitory Synapses

“…Furthermore, microtubules (van Zundert et al, 2002(van Zundert et al, , 2004 and F-actin disruptions alter GlyR stabilization at synapses, indicating that the cytoskeleton controls the number of inhibitory receptors at synapses. However, the number of synaptic GABA A R clusters is not modified in these conditions (Allison et al, 1998(Allison et al, , 2000 (but see Meyer et al, 2000;Petrini et al, 2003). It should be noted that cell types and quantification methods used in these studies differ.…”

The Mental Retardation Protein PAK3 Contributes to Synapse Formation and Plasticity in Hippocampus

“…Many of the filopodia-like protrusions induced by PAK3 dominant-negative mutation were devoid of postsynaptic densities or expressed only very small PSDs and/or lacked presynaptic partners. It is interesting in this respect that Rac1 signaling has also been implicated in receptor aggregation at inhibitory interneurons (Meyer et al, 2000) and that reduced kalirin expression was associated with a redistribution of PSD markers, as well as elimination of presynaptic endings (Ma et al, 2003). Furthermore, in Drosophila, PIX mutation is associated with defects in the stabilization of postsynaptic structures, an effect that involves a PAK homolog (Parnas et al, 2001).…”