Two Types of Novel Allosteric Modulators Activate β2-AR Signaling, a G Protein-coupled Receptor Involved in Airway Smooth Muscle Relaxation and Asthma♦


Papers of the Week

Two Types of Novel Allosteric Modulators Activate �2-AR
Signaling, a G Protein-coupled Receptor Involved in
Airway Smooth Muscle Relaxation and Asthma�
� See referenced article, J. Biol. Chem. 2014, 289, 35668 –35684

Development and Characterization of Pepducins as Gs-biased Allosteric Agonists

The �2-adrenergic receptor (�2AR) is
a G protein-coupled receptor (GPCR)
involved in hormonal signal transduc-
tion and plays a role in many physio-
logical processes including cardiac
muscle contraction and airway smooth
muscle relaxation. �-Agonists, which
stimulate the �2AR, are commonly
used as therapeutics in the treatment
of asthma. However, desensitization
of the receptor in response to �-ago-
nists, which is largely mediated by
GPCR kinases and �-arrestins, re-
duces agonist efficacy. An agonist
that can stimulate G protein signal-
ing through the �2AR while bypassing
GPCR kinases and �-arrestins may be
useful in the treatment of asthma. In
this Paper of the Week, a team led by
Jeffrey Benovic at Thomas Jefferson
University screened lipidated pep-
tides from the intracellular loops of
the �2AR, known as pepducins, and
discovered two types of biased activa-
tors of �2AR signaling. One type was
a receptor-dependent pepducin that
stabilized a conformation of the �2AR
that was biased towards the Gs het-
erotrimeric G protein while a second
group of pepducins directly activated
Gs. The investigators say that these
molecules “provide a valuable tool for
the continued study of �2AR function
and may prove useful as next-genera-
tion asthma therapeutics.”

DOI 10.1074/jbc.P114.618819

35685

Gs-biased agonists do not promote �2AR internalization or
desensitization.

This is an Open Access article under the CC BY license.

http://creativecommons.org/licenses/by/4.0/

	Papers of the Week: Two Types of Novel Allosteric Modulators Activate β2-AR Signaling, a G Protein-coupled Receptor Involved in Airway Smooth Muscle Relaxation and Asthma