Phosphodiesterases as Targets for Modulating T-Cell Responses - Phosphodiesterases as Drug Targets - page 350

that have been successfully used for treatment of male erectile dysfunction (Francis
and Corbin 2005 ) and have also been approved for the treatment of pulmonary
hypertension (reviewed in Vlachopoulos et al. 2009 ). PDE4-selective inhibitors
have shown potential for treatment of asthma and COPD, whereas the PDE3-
specific inhibitors have been approved for treatment of intermittent claudication
(reviewed in Conti and Beavo 2007 ; Houslay et al. 2005 ; Spina 2008 ; Thompson
et al. 2007 ).
In addition to PDE3, PDE4, and PDE7, T cells also express PDE1, PDE2, PDE5,
and PDE8 (reviewed in Essayan 2001 ). However, isoforms from the PDE4 subfam-
ily seem to represent the majority of cAMP hydrolyzing activity in T cells (Erdogan
and Houslay 1997 ; Giembycz et al. 1996 ). PDE4 isoforms are highly conserved
through evolution and four genes (PDE4A/B/C/D) encode over 20 distinct isoforms
(reviewed in Conti and Beavo 2007 ; Houslay et al. 2007 ; Houslay and Adams
2003 ). The PDE genes have complex structures including several intronic promo-
ters. In addition to alternate splicing, these promoters give rise to a number of
alternately initiated transcripts. The various PDE4 proteins are characterized by a
unique N-terminal region followed by the presence of upstream conserved regions
UPCR1 and/or UPCR2, resulting in long, short, and supershort PDE4 isoforms. It is
now becoming clear that these unique regions are important in intracellular target-
ing as well as for functional significance of individual isoforms (reviewed in Conti
and Beavo 2007 ; Houslay et al. 2007 ). Furthermore, an increasing list of proteins
have recently been shown to interact directly with various PDE4 isoforms, includ-
ing scaffolding proteins such as AKAPs, b -arrestin, and RACK1 and kinases such
as Erk and Src family tyrosine kinases (reviewed in Houslay 2009 ). These diverse
lists of interaction partners that sequester PDE4 isoforms clearly indicate that
targeting of these enzymes is very important. However, relatively little is still
known about the precise function of the different PDE4 isoforms, although
PDE4B1 has been linked to schizophrenia (Millar et al. 2005 ), PDE4D4 to prostate
cancer (Prins et al. 2008 ), and PDE4D7 to stroke (Gretarsdottir et al. 2003 ). PDE4
isoforms in complex with b -arrestin have recently been shown to have an important
role in T-cell activation and this is discussed in detail below.
1.3 TCR-Induced cAMP Production in T-Cell Lipid Rafts
TCR ligation has previously been demonstrated to induce cAMP production in
the cell (Ledbetter et al. 1986 ). However, since increased cAMP concentrations
inhibit T-cell function and proliferation (Aandahl et al. 2002 ; Skalhegg et al. 1992 ),
TCR-mediated cAMP production must be tightly regulated. The significance of
activation-induced cAMP production has still not been fully understood and the
spatiotemporal dynamics of the activation-induced cAMP gradient has not been
completely appreciated. However, we were able to show that upon engagement of
the TCR in primary T cells, cAMP was rapidly produced in lipid rafts (Abrahamsen
et al. 2004 ). This activates a pool of PKA targeted to rafts by association with the