Biology Reference
In-Depth Information
works ultimately at a molecular level, mainly by modulation of enzyme
activities that function together as a whole system to sense the balance of
energy coming in and energy required. The different organs in the body
have their own characteristic patterns of metabolism according to their func-
tions in the body. Thus, it is critical that metabolic pathways interact in a
dynamic sense, in the entire organism. Furthermore, the endocrine and ner-
vous systems need to precisely coordinate to control the flow of energy
within the body.
Much of the metabolic regulation is governed by hormones that are
delivered through the bloodstream and act through specific cellular recep-
tors. Both the cell-surface receptors (that usually bind peptide hormones)
and the nuclear receptors (that bind thyroid hormones, steroid hormones,
and other membrane-permeant ligands) play critical roles in metabolic reg-
ulation. Hormones acting through cell-surface receptors are involved in
rapid metabolic adjustments. These receptors signal via the small molecule
cyclic adenosine 3,5-monophosphate (cyclic AMP or cAMP) and the mem-
brane lipid phosphatidylinositol (3,4,5) trisphosphate. Following this, the
activities of downstream metabolic enzymes are regulated by covalent mod-
ification, especially phosphorylation and dephosphorylation, and/or translo-
cation of enzymes within the cell. Activation of the nuclear receptors by
their ligands, on the other hand, directly controls the transcription of met-
abolic genes and leads to long-term metabolic regulation.
Studies carried out with several different families of receptors have
pointed out that
b
-arrestins determine the specificity, spatiality, and tempo-
rality of cellular signals as well as the intracellular movement of receptors and
other signal complexes.
1-4
Binding of
b
-arrestins to ligand-bound
G protein-coupled receptors (GPCRs) physically uncouples the G protein
from the receptor and effectively terminates G protein-mediated signaling.
By coupling to a ligand-activated receptor,
b
-arrestins also initiate GPCR
signaling in a G protein-independent manner. Furthermore,
b
-arrestins
scaffold diverse signal complexes, thereby linking activated receptors with
distinct sets of accessory and effector proteins. Considering the intricate met-
abolic regulatory network composed of a variety of hormones and their
specific receptors, it should not be a surprise that proper functioning of
b
-arrestins is indispensable for the body's metabolic function. This chapter
summarizes the function of
b
-arrestins in metabolic regulation and also
discusses their association with metabolic syndromes including insulin resis-
tance, type 2 diabetes, and obesity.
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