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My name is Sergi Ferre,
I'm Senior Investigator at the National Institute on Drug Abuse,
and the title of my talk is
"Pre-Coupling of Receptor Oligomers and
Signaling Molecules: Challenging Classical Pharmacology".
I'm going to reveal the evidence we have
obtained from our work that supports the concepts
of pre-coupling and oligomerization of G-protein-coupled receptors, GPCR for short.
I believe our data and those from other research groups imply the need for
change in classical concepts of GPCR physiology and pharmacology.
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A G-protein-coupled receptor, GPCR for short,
a G-protein with its three subunits, alpha, beta,
and gamma, and adenylyl cyclase are
the three main elements of one of the most studied transmembrane cell-signaling pathways.
Since Gilman's classical conceptualization,
it has been generally assumed that these elements interact via collision coupling mode.
This implies that these are
freely mobile molecules able to couple sequentially by random collision.
A ligand binds to one molecule of GPCR,
which induces the binding and GTP- dependent activation of the G-protein,
which leads to its dissociation from the receptor
and dissociation of the alpha from the beta-gamma subunits.
Now, G-alpha subunit is free to bind to adenylyl cyclase,
which induces its activation or inhibition.
There are two subtypes of GS or stimulatory G-proteins,
with either GS or Golf alpha subunits.
There are five subtypes of GI or inhibitory G-proteins,
with either Gi1, Gi2,
Gi3, Go1 or Go2 alpha subunits.
The alpha subunit converts GTP into GDP,
and can then dissociate from
adenylyl cyclase and re-associate with the beta-gamma subunits,
ready for a new ligand-induced cycle of activation.
Two still controversial concepts are changing
