Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 314

to relate ligand-induced conformational changes in the receptor to ligand
“bias” for b arr versus G protein agonism. The b 2 AR interacts with
G proteins via its TM (transmembrane) helices V and VI, and intracellular
loops (ICLs) ICL2 and ICL3, but TM helix VII makes no substantial contact
with the G protein. Thus, the degree to which b 2 AR ligands shift the receptor
equilibrium toward the active state of TM helix VI dictates the resulting
G protein signaling capacity/efficacy. 119 For instance, the antagonist/weak
partial agonist alprenolol can induce a small shift on Cys 265 6.27 (TM VI),
but has a minimal effect on Cys 327 7.54 (TMVII), whereas the inverse agonist
carazolol induces no apparent shifts to either Cys. 119 Conversely, two b arr-
biased ligands, isoetharine and carvedilol, cause large conformational shifts
on Cys 327 7.54, while producing minimal changes at Cys 265 6.27. 119 Thus,
for the b 2 AR, it appears that TM helix VII conformations primarily impact
b arr signaling, whereas TM helix VI conformations G protein signaling. 119
The majority of known high-affinity b 2 AR ligands have a common struc-
tural motif consisting of an aromatic “head group” and an ethanolamine “tail
group” ( Fig. 12.1 ). The head group, that is, catechol, of agonists is directly
connected to the ethanolamine tail, while antagonists and inverse agonists,
both of which act as competitive inhibitors to agonists and either have no
impact or a negative impact on the basal receptor activity, have an additional
two-atom linker between the “head” and “tail” groups. Crystal structures of
the b 2 ARbound to various ligands, as well as biochemical and modeling stud-
ies, have established that the aromatic “head” groups interact with TMhelices
V and VI, whereas the ethanolamine “tails” are anchored by ionic and polar
interactions at TM helices III and VII. 119,120 Consequently, four different
types of b 2 AR ligands can be distinguished with regard to their b arr versus
G protein signaling “bias” properties ( Fig. 12.1 ):
Type 1.

Ligands that induce conformational activation of both TM helices
VI and VII and thus activate both G proteins and b arrs equally
(unbiased agonists), for example, isoproterenol, epinephrine,

and formoterol.

Type 2.

Ligands that block conformational activation of both TM helices
VI and VII and thus block both G proteins and b arrs equally

Figure 12.1 Cont'd — Bucindolol (based on its pharmacological similarity to carvedilol)
and nadolol are putative type 3 and type 4 b 2 AR ligands, respectively, that is, their types
have not been verified as yet. Right column: light pink indicates the R 1 substitution; light
blue, the biphenyl-methyl “ backbone ” ; and olive green, the tetrazole ring group. See

text for details.