  G-protein coupled receptors (GPCRs), a major gatekeeper of extracellular
signals on plasma membrane, are unarguably one of the most important
therapeutic targets. Given the recent discoveries of allosteric modulations, an
allosteric wiring diagram of intramolecular signal transductions would be of
great use to glean the mechanism of receptor regulation. Here, by evaluating
betweenness centrality ($C_B$) of each residue, we calculate maps of
information flow in GPCRs and identify key residues for signal transductions
and their pathways. Compared with preexisting approaches, the allosteric
hotspots that our $C_B$-based analysis detects for A$_{2A}$ adenosine receptor
(A$_{2A}$AR) and bovine rhodopsin are better correlated with biochemical data.
In particular, our analysis outperforms other methods in locating the rotameric
microswitches, which are generally deemed critical for mediating orthosteric
signaling in class A GPCRs. For A$_{2A}$AR, the inter-residue cross-correlation
map, calculated using equilibrium structural ensemble from molecular dynamics
simulations, reveals that strong signals of long-range transmembrane
communications exist only in the agonist-bound state. A seemingly subtle
variation in structure, found in different GPCR subtypes or imparted by agonist
bindings or a point mutation at an allosteric site, can lead to a drastic
difference in the map of signaling pathways and protein activity. The signaling
map of GPCRs provides valuable insights into allosteric modulations as well as
reliable identifications of orthosteric signaling pathways.
