Transcript Heterodimers of G protein

Heterodimers of
G protein-coupled
receptors
• G protein-coupled receptors
(GPCRs) exist as homodimers and
also associate with other GPCRs to
form heterodimers
• This association may alter the
function of both receptors,
yielding a distinct functional unit
examples
g-aminobutyric acid B (GABAB) receptors
that consist of GABAB1 and GABAB2 proteins
that are not functional when either one is
expressed alone
heterodimerization also leads to alterations
in ligand specificity: dimerization of T1R1 with
(T1R2 or T1R3)
Heterodimerization
and implications for drug design
• Development of ‘bivalent’ ligands that
specifically target the heterodimer
• Development of drug-like molecules that
specifically target the heterodimer
Heterodimerization leads to a change in
the binding pocket that could be specifically
targeted to develop heterodimer selective
drugs
Adenosine A2A and dopamine D2 receptors
in the dendritic spines of the striopallidal neuron
• In addition to dopamine and glutamate, the
neuromodulator adenosine plays an important
role in the function of striatal GABAergic efferent
neurons
Interactions between adenosine A2A and dopamine D2
receptors at the biochemical level
Direct protein–protein interaction between adenosine
A2A and dopamine D2 receptors
1. coimmunoprecipitation of both receptors
2.Bioluminescence energy transfer (BRET):the
first protein partner is fused to Renilla
luciferase and the second to a fluorescent
protein.
• BRET competition experiments were
performed using a chimeric D2–D1 receptor in
which the helices 5 and 6, the third
intracellular loop (I3) and the third
extracellular loop (E3) of the D2 receptor were
replaced by those of the dopamine D1
receptor.
A2A receptor–D2 receptor heterodimers
are preformed before being inserted into the
plasma membrane they are probably subject
to a dynamic regulation.
Finding out the mechanisms involved in this
regulation can have important implications for
the treatment of basal ganglia disorders,
schizophrenia and drug addiction.