Biology Reference
In-Depth Information
activation of the cAMP-dependent protein kinase A (PKA).
96
In the case of
the
b
2
AR, PKA can phosphorylate the intracellular loops of the receptor,
leading to a switch from G
a
stoG
a
i protein coupling which inhibits cAMP
production and affects the signaling outcome of receptor activation.
97
Of the different types of
a
-AR,
a
2A
ARs are the predominant subtype in
the CNS.
98-100
Presynaptic
a
2A
AR located in the locus coeruleus function
as key regulators of the noradrenergic system, controlling the synthesis and
release of NE and also the release of other neurotransmitters.
b
-AR are
expressed in both gray and white matter.
101-103
In the hippocampus,
b
-AR play an important role in regulating synaptic plasticity and memory
consolidation.
104,105
Almost all nuclei are positive for
b
1
AR and
b
2
AR.
106
Of the three types of
b
-AR expressed in astrocytes, the
b
2
AR
are the predominant one.
103,107-111
In astrocytes,
b
2
AR promote glucose
uptake though GLUT1 and accelerate glycogen degradation via coupling
to a G
a
s and cAMP-dependent pathway.
112
From a clinical point of view,
studies involving patients with depression have shown an upregulation of
a
2A
AR in the brain.
113-117
4.2. Noradrenergic receptors and GRK
As observed with other GPCR in transfected cells, after agonist stimulation,
the
a
2A
AR undergo rapid desensitization mediated by receptor phosphor-
ylation by GRK.
118,119
While
a
2A
AR phosphorylation appears to be depen-
dent on GRK2 and GRK3, the situation for the
a
2C
AR is less clear.
119,120
For this receptor, it seems that there is no agonist-induced promoted desen-
sitization nor phosphorylation by GRK2, 3, 5, or 6. The formation of
a
2A
AR-
a
2C
AR heterodimers has been observed in cells and the
a
2C
AR
component of the heterodimer seems to decrease the phosphorylation by
GRK and subsequent recruitment of
b
-arrestin 2. From a mechanistic point
of view, it appears that the
a
2A
AR conformation is less favorable for GRK2
phosphorylation when in an
a
2A
AR-
a
2C
AR heterodimer compared to a
a
2A
AR homodimer.
121
4.3. Arrestins and noradrenergic receptor internalization
As has been previously described for other GPCR, the rapid agonist-
induced desensitization of AR is driven by receptor phosphorylation and
the subsequent binding of
b
-arrestins. The relationship between receptor
phosphorylation by GRK and the ability to recruit
b
-arrestin 2 has been
clearly demonstrated in a
a
2A
AR-
a
2C
AR dimerization model.
121
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