Alterations in Expression and Function of Phosphodiesterases in Huntington’s Disease

Abstract

Cyclic AMP (cAMP, cyclic 3’, 5’-adenosine monophosphate) was first identified as a signalling molecule in 1958 (Rall & Sutherland, 1958), however it was not until 1962 that the enzyme responsible for hydrolysis of cAMP was identified and named phosphodiesterase (PDE; Butcher & Sutherland, 1962). Shortly afterwards, cyclic GMP (cGMP, cyclic 3’, 5’-guanosine monophosphate) was identified as another important second messenger that was hydrolyzed by PDE (Ashman et al., 1963). PDEs inactivate cAMP or cGMP by hydrolizing the 3’ cyclic phosphate bond of the cyclic nucleotide in question (Bender & Beavo 2006). Through molecular cloning and sequencing, it is now known that mammalian PDEs are encoded by 21 distinct genes (Bender & Beavo, 2006). These 21 genes encode protein isoforms of which variants can exist through the use of multiple transcription start sites and alternative mRNA splicing (Bender & Beavo, 2006). The 21 identified isoforms have been grouped into 11 families based on similarities in amino acid sequence, structure and function.