GABA(B2) is essential for g-protein coupling of the GABA(B) receptor heterodimer.
GABA(B) receptors are unique among G-protein-coupled receptors (GPCRs) in their requirement for heterodimerization between two homologous subunits, GABA(B1) and GABA(B2), for functional expression. Whereas GABA(B1) is capable of binding receptor agonists and antagonists, the role of each GABA(B) subunit in receptor signaling is unknown. Here we identified amino acid residues within the second intracellular domain of GABA(B2) that are critical for the coupling of GABA(B) receptor heterodimers to their downstream effector systems. Our results provide strong evidence for a functional role of the GABA(B2) subunit in G-protein coupling of the GABA(B) receptor heterodimer. In addition, they provide evidence for a novel "sequential" GPCR signaling mechanism in which ligand binding to one heterodimer subunit can induce signal transduction through the second partner of a heteromeric complex.
Robbins
M J
MJ
Department Psychiatry CEDD, GlaxoSmithKline Pharmaceuticals, Harlow, Essex CM19 5AW, United Kingdom.
Calver
A R
AR
Filippov
A K
AK
Hirst
W D
WD
Russell
R B
RB
Wood
M D
MD
Nasir
S
S
Couve
A
A
Brown
D A
DA
Moss
S J
SJ
Pangalos
M N
MN
D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D019281:Dimerization; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008845:Microinjections; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits; D051381:Rats; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020539:Sequence Analysis, Protein; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000378:metabolism; D014162:Transfection
D000596:Amino Acids; C485503:GABBR2 protein, human; C116566:Gabbr2 protein, rat; D021122:Protein Subunits; D018079:Receptors, GABA; D018080:Receptors, GABA-B; D011993:Recombinant Fusion Proteins; D019204:GTP-Binding Proteins; D002118:Calcium