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C. Limatola - Molecular and functional approaches to investigate the physiopathological role of the chemokines
now extending these results trying to define how
general is the importance of AR1 in the neuroprotective
mechanisms induced by different neurotrophins
like brain-derived neurotrophic factor,
erythropoietin, interleukin-6.
Neuromodulatory activity of CXCL8
Among the many chemokines and chemokine receptors
discovered in the last few years, the chemokine
CXCL8 and its receptor CXCR2 are particularly
interesting, being expressed in the brain both on
neurons and glial cells (Tran and Miller, 2003) and
playing neuromodulatory roles in synaptic transmission
(Meucci et al., 1998; Ragozzino et al., 1998;
Giovannelli et al., 1998; Xiong et al., 2003; Lax et al.,
2002; Puma et al., 2001), important roles during
oligodendrocyte development, proliferation and
recruitment to MS lesions (Robinson et al., 1998;
Omari et al., 2006) and protective activities towards
neurons and astrocytes (Limatola et al., 2000; Saas et
al., 2002; Wang et al., 2007; Watson and Fan, 2005).
We have recently demonstrated that CXCR2 expression
and activation mediates the modulation of
AMPA-type glutamate receptors (GluR) properties,
changing AMPAR affinity, binding site cooperativity,
and channel opening probability (Lax et al., 2002).
Furthermore, the mutual interaction between GluR1
and CXCR2 determines the signaling properties of
CXCR2, possibly due to alterations in the ability of
CXCR2 to holigomerize (Trettel et al., 2003).
AMPA receptors are responsible for the majority of
excitatory synaptic transmission in the brain. It is
well established that protein phosphorylation regulates
ion channel functional properties of the
tetrameric AMPARs (Song and Huganir, 2002).
There are at least ten phosphorylation sites on the
intracellular carboxy-terminal domain of GluR1-
GluR4 subunits, two of which on the GluR1 subunit,
serine 831 (S831) and serine 845 (S845) have been
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extensively characterized. Specifically, S831 is phosphorylated
by CAMKII and protein kinase C (PKC),
while S845 is phosphorylated by cAMP-dependent
protein kinase (PKA), and their phosphorylation
potentiates the function of the homomeric GluR1
(Banke et al., 2000). We investigate whether the activation
of CXCR2, that yields a gain-of-function of
the homomeric GluR1 (Ragozzino et al., 1998;
Giovannelli et al., 1998; Limatola et al., 2002), was
associated with receptor phosphorylation, and if the
described physical and functional interactions
between these two receptors could be mediated, at
least in part, by the phosphorylation of GluR1 on
S845 and/or S831. We have demonstrated that
CXCL8 induces GluR1 phosphorylation on neurons
and transfected cells and the importance of GluR1
phosphorylation on S845 and/or S831 (assessed by S
replacement with A or E) in modulating the physical
and functional interaction between GluR1 and
CXCR2 (Catalano et al., 2008).
Selected publications
Limatola C, Massa V, Lauro C, Catalano M,
Giovannetti A, Nuccitelli S, Spinedi A. Evidence for
a role of glycosphingolipids in CXCR4-dependent
cell migration. FEBS Letters 2007, 581:2641-6.
Catalano M, Trettel F, Cipriani R, Lauro C, Sobrero
F, Eusebi F, Limatola C. Chemokine CXCL8 modulates
GluR1 phosphorylation. J Neuroimmunol. 2008,
198:75-81.
Lauro C, Di Angelantonio S, Cipriani R, Sobrero F,
Antonilli L, Brusadin V, Ragazzino D, Limatola C.
Activity of adenosine receptors type 1 is required for
CX 3 CL1-mediated neuroprotection and neuromodulation
in hippocampal neurons. J Immunol. 2008,
180:7590-6.