Although nonsense and missense PDE11A variants were found in 20% of patients with acromegaly, there was no significant difference in variant frequency compared with controls, suggesting that these variants are unlikely to contribute to the pathogenesis of GH-secreting adenomas since the conservation of the wild-type allele of PDE11A remains in the majority of tumor samples and no significant clinical phenotype could be observed in patients with variant PDE11A (13). Interestingly, although PDE8B was not detected in normal pituitary, this isoform was shown to be overexpressed in all MK 886 GH-secreting adenomas, especially higher levels were observed in mutations in somatotrophinomas (14). PDE4A Family and AIP Compared to other PDE isoforms, human PDE4A4 is specifically associated with AIP (also called XAP2 or ARA9), a co-chaperone of HSP90 and HSC70 (26, 35). into the second messenger cAMP. cAMP activates a cascade of other enzymes, thus amplifying the cellular reaction (3). Following GHRH activation of somatotrophs cAMP binds the regulatory subunit of protein kinase A Rabbit polyclonal to APBA1 (PKA) (3, 6). The activated catalytic subunit of PKA then phosphorylate a series of targets that regulate effector enzymes, ion channels, and activate the transcription of specific genes that mediate cell growth and differentiation. Additional effectors of cAMP include the exchange factor regulated by cAMP (EPAC) protein, cyclic nucleotide-gated ion channels, Popeye proteins, and possibly additional targets that are still under investigation (1, 8). Open in a separate window Figure 1 The role of phosphodiesterases (PDEs) in the pituitary gland: After stimulation of somatotroph cells via GHRH, the G protein coupled receptor is activated, which causes a conformational change of the receptor. The Gs subunit detaches from the complex, and binds to adenylyl cyclase, which catalyzes the conversion of ATP to cAMP. Elevation of intracellular cAMP leads to dissociation of the catalytic subunit and the regulatory subunit of protein kinase A (PKA). Activation MK 886 of protein MK 886 kinase A can then phosphorylate a number of targets that regulate effector enzymes and ion channels as well as activates gene transcription that play a MK 886 role in cell growth and differentiation. PDEs are fundamental in regulating this pathway, since they are the only enzymes capable of hydrolyzing cAMP to its inactive 5′-AMP form. PDE4A, PDE4B, PDE4C, PDE4D, PDE8B, and PDE11A are increased in GH-secreting adenomas, possibly as a compensatory mechanism. However, and mutations interfere with the expression of these PDEs. PDEs act as regulators of the cAMP pathway, as they are capable of hydrolyzing cAMP to its inactive 5′-AMP form, which is the main pathway for inactivation of cAMP (3, 6). As a consequence, cAMP can either suppress cell proliferation and the mitogenic action of growth factors in some cell types, or conversely, promote the transition from cell cycle G0 to G1 and stimulate cell growth in others (9, 10). It is unclear, for example, why cAMP has a proliferative role in the somatotroph cells while an anti-proliferative role in gonadotroph cells (6, 9, 10). cAMP signaling is temporally, spatially, and functionally regulated by compartmentalization and influenced by a complex network of cell- and tissue-specific downstream effectors and regulators (11). In the pituitary, cAMP acts as a key signaling molecule that controls responsiveness to mitogens and secretagogues, such as hypothalamic hormones, neurotransmitters, and other peripheral factors (7) and a dysregulated cAMP-pathway is involved in the pathogenesis and response to therapy of pituitary adenomas (11). PDEs are directly implicated in various endocrine disorders affecting the pituitary, adrenals, thyroid, testes, and ovaries (3). Little is known about the expression of PDE isoforms in the pituitary gland, especially in humans, since the vast majority of studies on the association between PDEs and endocrine functions have been performed or in animals. mRNA studies have implicated PDE1, PDE2, PDE4, and PDE11A as being the most highly expressed PDEs in the pituitary (3, 12C14). Interestingly, PDE4 is the only selective PDE for cAMP. The discovery of the physiological role of PDEs in the human pituitary has been hindered due to the lack of availability of specific antibodies. In addition, mRNA does MK 886 not always reflect the protein amount or function due to variations in translation, protein stability, or posttranslational modifications. PDE4 isoforms in mammals are encoded by four different genes (PDE4A, PDE4B, PDE4C, and PDE4D) and each of these genes encodes multiple isoforms, through the use of specific promoters for each isoform and alternative messenger RNA processing (15C17). PDE4s differ from the other PDE families by their specific catalytic regions (15C17), as well as by the presence of two signature regions called upstream conserved regions (UCRs), which are located in the N-terminal third of the proteins and referred to as UCR1 and UCR2 (18). The various isoforms encoded by each of the PDE4A, PDE4B, PDE4C, and PDE4D genes are divided into three groups: ‘long’ isoforms that contain both UCR1 and UCR2, short isoforms that do not have UCR1 but include UCR2,.