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The Journal of Neuroscience, April 15, 2000, 20(8):2867-2874

Heteromeric Assembly of GABA_BR1 and GABA_BR2 Receptor Subunits Inhibits Ca²⁺ Current in Sympathetic Neurons

Alexander K. Filippov¹, Andrés Couve^{1, 2}, Menelas N. Pangalos³, Frank S. Walsh³, David A. Brown¹, and Stephen J. Moss^{1, 2}

¹ Department of Pharmacology and ² Medical Research Council Laboratory of Molecular Cell Biology, University College London, London WC1E 6BT, United Kingdom, and ³ Department of Neuroscience, Smith-Kline Beecham, Harlow, Essex CM19 5AW, United Kingdom

Neuronal GABA_B receptors regulate calcium and potassium currents via G-protein-coupled mechanisms and play a critical role in long-term inhibition of synaptic transmission in the CNS. Recent studies have demonstrated that assembly of GABA_B receptor GABA_BR1 and GABA_BR2 subunits into functional heterodimers is required for coupling to potassium channels in heterologous systems. However whether heterodimerization is required for the coupling of GABA_B receptors to effector systems in neurons remains to be established. To address this issue, we have studied the coupling of recombinant GABA_B receptors to endogenous Ca²⁺ channels in superior cervical ganglion (SCG) neurons using nuclear microinjection to introduce both sense and antisense expression constructs. Patch-clamp recording from neurons injected with both GABA_BR1a/1b and GABA_BR2 cDNAs or with GABA_BR2 alone produced marked baclofen-mediated inhibition of Ca²⁺ channel currents via a pertussis toxin-sensitive mechanism. The actions of baclofen were blocked by CGP62349, a specific GABA_B antagonist, and were voltage dependent. Interestingly, SCGs were found to express abundantly GABA_BR1 but not GABA_BR2 at the protein level. To determine whether heterodimerization of GABA_BR1 and GABA_BR2 subunits was required for Ca²⁺ inhibition, the GABA_BR2 expression construct was microinjected with a GABA_BR1 antisense construct. This resulted in a dramatic decrease in the levels of the endogenous GABA_BR1 protein and a marked reduction in the inhibitory effects of baclofen on Ca²⁺ currents. Therefore our results suggest that in neurons heteromeric assemblies of GABA_BR1 and GABA_BR2 are essential to mediate GABAergic inhibition of Ca²⁺ channel currents.

Key words: GABA_BR1; GABA_BR2; Ca²⁺ channel; sympathetic neuron; antisense; G-protein

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2082867-08$05.00/0

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