 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
Previous Article | Next Article
The Journal of Neuroscience, February 15, 2001, 21(4):1203-1210
The C-Terminal Domains of the GABAB Receptor Subunits Mediate Intracellular Trafficking But Are Not Required for Receptor Signaling
Andrew R. Calver1, Melanie J. Robbins1, Christophe Cosio1, Simon Q. J. Rice2, Adam J. Babbs1, Warren D. Hirst1, Izzy Boyfield1, Martyn D. Wood1, Robert B. Russell3, Gary W. Price1, Andrés Couve4, Stephen J. Moss4, and Menelas N. Pangalos1 Departments of 1 Neuroscience Research and 2 Biotechnology and Genetics and 3 Bioinformatics Research Group, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex CM19 5AW, United Kingdom, and 4 Medical Research Council Laboratory for Molecular Cell Biology and Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom
GABAB receptors are G-protein-coupled receptors that mediate slow synaptic inhibition in the brain and spinal cord. These receptors are heterodimers assembled from GABAB1 and GABAB2 subunits, neither of which is capable of producing functional GABAB receptors on homomeric expression. GABAB1, although able to bind GABA, is retained within the endoplasmic reticulum (ER) when expressed alone. In contrast, GABAB2 is able to access the cell surface when expressed alone but does not couple efficiently to the appropriate effector systems or produce any detectable GABA-binding sites. In the present study, we have constructed chimeric and truncated GABAB1 and GABAB2 subunits to explore further GABAB receptor signaling and assembly. Removal of the entire C-terminal intracellular domain of GABAB1 results in plasma membrane expression without the production of a functional GABAB receptor. However, coexpression of this truncated GABAB1 subunit with either GABAB2 or a truncated GABAB2 subunit in which the C terminal has also been removed is capable of functional signaling via G-proteins. In contrast, transferring the entire C-terminal tail of GABAB1 to GABAB2 leads to the ER retention of the GABAB2 subunit when expressed alone. These results indicate that the C terminal of GABAB1 mediates the ER retention of this protein and that neither of the C-terminal tails of GABAB1 or GABAB2 is an absolute requirement for functional coupling of heteromeric receptors. Furthermore although GABAB1 is capable of producing GABA-binding sites, GABAB2 is of central importance in the functional coupling of heteromeric GABAB receptors to G-proteins and the subsequent activation of effector systems.
Key words: GABAB; GPCR; trafficking; signaling; intracellular retention; G-protein coupling; chimeras; receptor subunits
Copyright © 2001 Society for Neuroscience 0270-6474/01/2141203-08$05.00/0
This article has been cited by other articles:
O. A. Ramirez, R. L. Vidal, J. A. Tello, K. J. Vargas, S. Kindler, S. Hartel, and A. Couve
Dendritic Assembly of Heteromeric {gamma}-Aminobutyric Acid Type B Receptor Subunits in Hippocampal Neurons
J. Biol. Chem., May 8, 2009; 284(19): 13077 - 13085.
[Abstract] [Full Text] [PDF]
Y. Jiang, L. Borrelli, B. J. Bacskai, Y. Kanaoka, and J. A. Boyce
P2Y6 Receptors Require an Intact Cysteinyl Leukotriene Synthetic and Signaling System to Induce Survival and Activation of Mast Cells
J. Immunol., January 15, 2009; 182(2): 1129 - 1137.
[Abstract] [Full Text] [PDF]
R. Nomura, Y. Suzuki, A. Kakizuka, and H. Jingami
Direct Detection of the Interaction between Recombinant Soluble Extracellular Regions in the Heterodimeric Metabotropic {gamma}-Aminobutyric Acid Receptor
J. Biol. Chem., February 22, 2008; 283(8): 4665 - 4673.
[Abstract] [Full Text] [PDF]
C. Brock, N. Oueslati, S. Soler, L. Boudier, P. Rondard, and J.-P. Pin
Activation of a Dimeric Metabotropic Glutamate Receptor by Intersubunit Rearrangement
J. Biol. Chem., November 9, 2007; 282(45): 33000 - 33008.
[Abstract] [Full Text] [PDF]
Y. Jiang, L. A. Borrelli, Y. Kanaoka, B. J. Bacskai, and J. A. Boyce
CysLT2 receptors interact with CysLT1 receptors and down-modulate cysteinyl leukotriene dependent mitogenic responses of mast cells
Blood, November 1, 2007; 110(9): 3263 - 3270.
[Abstract] [Full Text] [PDF]
A. M. Pooler and R. A. J. McIlhinney
Lateral Diffusion of the GABAB Receptor Is Regulated by the GABAB2 C Terminus
J. Biol. Chem., August 31, 2007; 282(35): 25349 - 25356.
[Abstract] [Full Text] [PDF]
T. K. Best, R. J. Siarey, and Z. Galdzicki
Ts65Dn, a Mouse Model of Down Syndrome, Exhibits Increased GABAB-Induced Potassium Current
J Neurophysiol, January 1, 2007; 97(1): 892 - 900.
[Abstract] [Full Text] [PDF]
D. Bao, Z. Pang, M. A. Morgan, J. Parris, Y. Rong, L. Li, and J. I. Morgan
Cbln1 Is Essential for Interaction-Dependent Secretion of Cbln3
Mol. Cell. Biol., December 15, 2006; 26(24): 9327 - 9337.
[Abstract] [Full Text] [PDF]
M. W. Fleck
Glutamate Receptors and Endoplasmic Reticulum Quality Control: Looking beneath the Surface
Neuroscientist, June 1, 2006; 12(3): 232 - 244.
[Abstract] [PDF]
M. C. Overton, S. L. Chinault, and K. J. Blumer
Oligomerization of G-Protein-Coupled Receptors: Lessons from the Yeast Saccharomyces cerevisiae
Eukaryot. Cell, December 1, 2005; 4(12): 1963 - 1970.
[Full Text] [PDF]
C. Brock, L. Boudier, D. Maurel, J. Blahos, and J.-P. Pin
Assembly-dependent Surface Targeting of the Heterodimeric GABAB Receptor Is Controlled by COPI but Not 14-3-3
Mol. Biol. Cell, December 1, 2005; 16(12): 5572 - 5578.
[Abstract] [Full Text] [PDF]
S. C. Prinster, C. Hague, and R. A. Hall
Heterodimerization of G Protein-Coupled Receptors: Specificity and Functional Significance
Pharmacol. Rev., September 1, 2005; 57(3): 289 - 298.
[Abstract] [Full Text] [PDF]
K. Kanbara, K. Okamoto, S. Nomura, T. Kaneko, R. Shigemoto, H. Azuma, Y. Katsuoka, and M. Watanabe
Cellular Localization of GABA and GABAB Receptor Subunit Proteins During Spermiogenesis in Rat Testis
J Androl, July 1, 2005; 26(4): 485 - 493.
[Abstract] [Full Text] [PDF]
P.-Y. Law, L. J. Erickson-Herbrandson, Q. Q. Zha, J. Solberg, J. Chu, A. Sarre, and H. H. Loh
Heterodimerization of {micro}- and {delta}-Opioid Receptors Occurs at the Cell Surface Only and Requires Receptor-G Protein Interactions
J. Biol. Chem., March 25, 2005; 280(12): 11152 - 11164.
[Abstract] [Full Text] [PDF]
S. J. Mah, E. Cornell, N. A. Mitchell, and M. W. Fleck
Glutamate Receptor Trafficking: Endoplasmic Reticulum Quality Control Involves Ligand Binding and Receptor Function
J. Neurosci., March 2, 2005; 25(9): 2215 - 2225.
[Abstract] [Full Text] [PDF]
L. Silvotti, G. Giannini, and R. Tirindelli
The Vomeronasal Receptor V2R2 Does Not Require Escort Molecules for Expression in Heterologous Systems
Chem Senses, January 1, 2005; 30(1): 1 - 8.
[Abstract] [Full Text] [PDF]
V. Binet, C. Brajon, L. Le Corre, F. Acher, J.-P. Pin, and L. Prezeau
The Heptahelical Domain of GABAB2 Is Activated Directly by CGP7930, a Positive Allosteric Modulator of the GABAB Receptor
J. Biol. Chem., July 9, 2004; 279(28): 29085 - 29091.
[Abstract] [Full Text] [PDF]
M. Gassmann, H. Shaban, R. Vigot, G. Sansig, C. Haller, S. Barbieri, Y. Humeau, V. Schuler, M. Muller, B. Kinzel, et al.
Redistribution of GABAB(1) Protein and Atypical GABAB Responses in GABAB(2)-Deficient Mice
J. Neurosci., July 7, 2004; 24(27): 6086 - 6097.
[Abstract] [Full Text] [PDF]
B. Bettler, K. Kaupmann, J. Mosbacher, and M. Gassmann
Molecular Structure and Physiological Functions of GABAB Receptors
Physiol Rev, July 1, 2004; 84(3): 835 - 867.
[Abstract] [Full Text] [PDF]
D. Yin, S. Gavi, H.-y. Wang, and C. C. Malbon
Probing Receptor Structure/Function with Chimeric G-Protein-Coupled Receptors
Mol. Pharmacol., June 1, 2004; 65(6): 1323 - 1332.
[Abstract] [Full Text] [PDF]
J. Liu, D. Maurel, S. Etzol, I. Brabet, H. Ansanay, J.-P. Pin, and P. Rondard
Molecular Determinants Involved in the Allosteric Control of Agonist Affinity in the GABAB Receptor by the GABAB2 Subunit
J. Biol. Chem., April 16, 2004; 279(16): 15824 - 15830.
[Abstract] [Full Text] [PDF]
B. P. Fairfax, J. A. Pitcher, M. G. H. Scott, A. R. Calver, M. N. Pangalos, S. J. Moss, and A. Couve
Phosphorylation and Chronic Agonist Treatment Atypically Modulate GABAB Receptor Cell Surface Stability
J. Biol. Chem., March 26, 2004; 279(13): 12565 - 12573.
[Abstract] [Full Text] [PDF]
G. E. Breitwieser
G Protein-Coupled Receptor Oligomerization: Implications for G Protein Activation and Cell Signaling
Circ. Res., January 9, 2004; 94(1): 17 - 27.
[Abstract] [Full Text] [PDF]
J. Mundschenk, N. Unger, S. Schulz, V. Hollt, S. Schulz, R. Steinke, and H. Lehnert
Somatostatin Receptor Subtypes in Human Pheochromocytoma: Subcellular Expression Pattern and Functional Relevance for Octreotide Scintigraphy
J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5150 - 5157.
[Abstract] [Full Text] [PDF]
M. C. Overton and K. J. Blumer
The Extracellular N-terminal Domain and Transmembrane Domains 1 and 2 Mediate Oligomerization of a Yeast G Protein-coupled Receptor
J. Biol. Chem., October 25, 2002; 277(44): 41463 - 41472.
[Abstract] [Full Text] [PDF]
J. Kniazeff, T. Galvez, G. Labesse, and J.-P. Pin
No Ligand Binding in the GB2 Subunit of the GABAB Receptor Is Required for Activation and Allosteric Interaction between the Subunits
J. Neurosci., September 1, 2002; 22(17): 7352 - 7361.
[Abstract] [Full Text] [PDF]
M. Havlickova, L. Prezeau, B. Duthey, B. Bettler, J.-P. Pin, and J. Blahos
The Intracellular Loops of the GB2 Subunit Are Crucial for G-Protein Coupling of the Heteromeric gamma -Aminobutyrate B Receptor
Mol. Pharmacol., August 1, 2002; 62(2): 343 - 350.
[Abstract] [Full Text] [PDF]
N. G. Bowery, B. Bettler, W. Froestl, J. P. Gallagher, F. Marshall, M. Raiteri, T. I. Bonner, and S. J. Enna
International Union of Pharmacology. XXXIII. Mammalian gamma -Aminobutyric AcidB Receptors: Structure and Function
Pharmacol. Rev., June 1, 2002; 54(2): 247 - 264.
[Abstract] [Full Text] [PDF]
S. Grunewald, B. J. Schupp, S. R. Ikeda, R. Kuner, F. Steigerwald, H.-C. Kornau, and G. Kohr
Importance of the gamma -Aminobutyric AcidB Receptor C-Termini for G-Protein Coupling
Mol. Pharmacol., May 1, 2002; 61(5): 1070 - 1080.
[Abstract] [Full Text] [PDF]
B. Duthey, S. Caudron, J. Perroy, B. Bettler, L. Fagni, J.-P. Pin, and L. Prezeau
A Single Subunit (GB2) Is Required for G-protein Activation by the Heterodimeric GABAB Receptor
J. Biol. Chem., January 25, 2002; 277(5): 3236 - 3241.
[Abstract] [Full Text] [PDF]
M. Margeta-Mitrovic, Y. N. Jan, and L. Y. Jan
Function of GB1 and GB2 subunits in G protein coupling of GABAB receptors
PNAS, November 20, 2001; (2001) 251554498.
[Abstract] [Full Text] [PDF]
J.-P. Pin, M.-L. Parmentier, and L. Prezeau
Positive Allosteric Modulators for gamma -Aminobutyric AcidB Receptors Open New Routes for the Development of Drugs Targeting Family 3 G-Protein-Coupled Receptors
Mol. Pharmacol., November 1, 2001; 60(5): 881 - 884.
[Full Text] [PDF]
M. J. Robbins, A. R. Calver, A. K. Filippov, W. D. Hirst, R. B. Russell, M. D. Wood, S. Nasir, A. Couve, D. A. Brown, S. J. Moss, et al.
GABAB2 Is Essential for G-Protein Coupling of the GABAB Receptor Heterodimer
J. Neurosci., October 15, 2001; 21(20): 8043 - 8052.
[Abstract] [Full Text] [PDF]
D. B. Scott, T. A. Blanpied, G. T. Swanson, C. Zhang, and M. D. Ehlers
An NMDA Receptor ER Retention Signal Regulated by Phosphorylation and Alternative Splicing
J. Neurosci., May 1, 2001; 21(9): 3063 - 3072.
[Abstract] [Full Text] [PDF]
M. Margeta-Mitrovic, Y. N. Jan, and L. Y. Jan
Function of GB1 and GB2 subunits in G protein coupling of GABAB receptors
PNAS, December 4, 2001; 98(25): 14649 - 14654.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|