PDE8B

PDE8B plays a role in:

• Thyroid function and helps determine the level of TSH.  Higher PDE8B should cause lower TSH.  
• Alzheimer's. PED8B is increased in certain brain regions.
• Insulin secretion
• Adrenal disorders

Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in specific signaling in the thyroid gland.

PDE8B gene

PDE8B gene is member of the PDE8 family (variants PDE8A and PDE8B) [R]

Products of PDE8B gene is enzyme phosphodiesterase 8B (PDE8B) (also known as ADSD; PPNAD3) [R]. The PDE8B gene is produced most abundantly in the thyroid gland (where it has threefold higher levels than in the next highest tissue) [R]. The product of PDE8B can be detected in both human and mouse adrenal glands [R1, R2]. It is expressed at lower levels in some other tissues including the brain, spinal cord, and placenta [R1]. [R2]

PDE8 gene product was found in liquid part of cells (cytosolic) [R1]. [R2]

Mechanism

The phosphodiesterase 8B (PDE8B) plays crucial roles in controlling the concentration of chemical cyclic adenosine monophosphate (cAMP) in cells.[R]

PDE8B has the highest attraction for cAMP out of any known phosphodiesterase; PDE8B would be active even at low concentrations of cAMP [R1] [R2].

The PDE8B chemically destroys cAMP. [R1], [R2], [R3], [R4].

cAMP is regulating many important physiological processes (including cell proliferation and apoptosis, myocardial contractility, vascular and airway smooth muscle relaxation, reproduction, immune/ inflammatory responses, visual transduction, secretion, bone development, etc.). [R]

Conversely, chemical destroying of cAMP plays key roles in the development of some diseases and clinically relevant disease states (including obesity, diabetes, heart failure, pulmonary hypertension, erectile dysfunction, chronic obstructive pulmonary disease (COPD), arthritis, certain forms of retinal degeneration, and cancer, etc). [R1], [R2], [R3], [R3], [R4], [R5].

PDE8B associated with production of steroid hormones:

PBE8B associated with chemical destroying of cAMP and with the production of steroid hormones in adrenal glands. [R1].

The cAMP activates cAMP-dependent protein kinase (PKA), which in turn promotes the production of steroid hormones by different mechanisms (acute and chronic). [R1], [R2], [R3]

PDE8B is associated with some adrenal diseases:

• micronodular adrenocortical hyperplasia (MAH) leading to Cushing syndrome (CS) (a heterozygous missense mutation). [R1], [R2]

• adrenocortical tumors. [R].

• Cushing syndrome (CS). [R1], [R2]

• severe adrenal hyperplasia (mutation His350Pro). [R].

• autosomal dominant striatal degeneration (ADSD). [R]

PDE8B is implicated in thyroids functions.

PDE8B is implicated in thyroid diseases:

• autonomous thyroid adenomas. PDE8B activity has been detected in autonomous thyroid adenomas, where it may represent a compensatory mechanism opposing the constitutive activation of the cAMP pathway. [R]

The PDE8B associated with chemical destroying of cyclic adenosine monophosphate (cAMP) in the thyroid gland, it results in decreased production of thyroid hormone (T4 and T3). The decrease of thyroid hormones (T4 and T3) level results in an increase of thyroid-stimulating hormone (TSH) level. [R]

TSH interacts with the TSH receptor (TSHR) on thyroid cells and via interaction with the chemical, cAMP controls the production of thyroid hormones (T4 and T3), causing the growth of thyroid cells on a longer time scale. [R1], [R2].

When the levels of hormones T3 and T4 are low, the production of hormones TRH and TSH increases, and conversely, when the level of hormones T3 and T4 are high, TRH and TSH hormones production decreases. [R]

The level of TSH in blood is a sensitive indicator of thyroid function which can show abnormalities leading to common endocrine disorders. [R]

PDE8B is implicated in others:

• Alzheimer’s disease (AD). PDE8B production was significantly increased in some brain areas (cortical areas and parts of the hippocampal formation). The production of PDE8B is associated with the stages of the Alzheimer’s disease. [R1] [R2]

• pituitary adenomas (hypophysis.adenomas). Production of PDE8B was absent in the normal brain (pituitary part of the brain) but detectable in almost all adenomas with mutation of PDE8B. [R]

• increasing of insulin production in pancreatic cells of rats. [R]

     From NCBI Gene: Pigmented nodular adrenocortical disease, primary, 3Striatal degeneration, autosomal dominantFrom UniProt: Primary pigmented nodular adrenocortical disease 3 (PPNAD3): A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. [MIM:614190] Striatal degeneration, autosomal dominant 1 (ADSD1): A movement disorder affecting the striatal part of the basal ganglia and characterized by bradykinesia, dysarthria and muscle rigidity. These symptoms resemble idiopathic Parkinson disease, but tremor is not present. [MIM:609161]

     From NCBI Gene: The protein encoded by this gene is a cyclic nucleotide phosphodiesterase (PDE) that catalyzes the hydrolysis of the second messenger cAMP. The encoded protein, which does not hydrolyze cGMP, is resistant to several PDE inhibitors. Defects in this gene are a cause of autosomal dominant striatal degeneration (ADSD). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2010] From UniProt: Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in specific signaling in the thyroid gland.

Potential fixes:

PDE8 may be a potential therapeutic target for the treatment by selective inhibitor [R].

Inhibitors:

PDE8B is insensitive to PDE inhibitors (IBMX,  methylxanthines, theophylline, caffeine). [R1], [R2], [R3], [R4], [R5];