GABAB receptor association with the PDZ scaffold Mupp1 alters receptor stability and function.
gamma-Aminobutyric acid, type B (GABA(B)) receptors are heterodimeric G protein-coupled receptors that mediate slow inhibitory synaptic transmission in the central nervous system. To identify novel interacting partners that might regulate GABA(B) receptor (GABA(B)R) functionality, we screened the GABA(B)R2 carboxyl terminus against a recently created proteomic array of 96 distinct PDZ (PSD-95/Dlg/ZO-1 homology) domains. The screen identified three specific PDZ domains that exhibit interactions with GABA(B)R2: Mupp1 PDZ13, PAPIN PDZ1, and Erbin PDZ. Biochemical analysis confirmed that full-length Mupp1 and PAPIN interact with GABA(B)R2 in cells. Disruption of the GABA(B)R2 interaction with PDZ scaffolds by a point mutation to the carboxyl terminus of the receptor dramatically decreased receptor stability and attenuated the duration of GABA(B) receptor signaling. The effects of mutating the GABA(B)R2 carboxyl terminus on receptor stability and signaling were mimicked by small interference RNA knockdown of endogenous Mupp1. These findings reveal that GABA(B) receptor stability and signaling can be modulated via GABA(B)R2 interactions with the PDZ scaffold protein Mupp1, which may contribute to cell-specific regulation of GABA(B) receptors in the central nervous system.
Balasubramanian
Srividya
S
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Fam
Sami R
SR
Hall
Randy A
RA
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D015815:Cell Adhesion Molecules; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D020543:Proteome / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C413364:ERBIN protein, human; C485503:GABBR2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C111442:MPDZ protein, human; D008565:Membrane Proteins; C491749:Mpdz protein, rat; D009363:Neoplasm Proteins; C423943:PDZD2 protein, human; C414604:PDZD2 protein, rat; D020543:Proteome; D018080:Receptors, GABA-B; C517630:erbin protein, rat