Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

Abstract

By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. Since these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multi-molecular signaling/regulatory complexes called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners.

Kv7.5 Potassium Channel Subunits Are the Primary Targets for PKA-Dependent Enhancement of Vascular Smooth Muscle Kv7 Currents

“…Of the known members of the heterogeneous PDE superfamily (PDE1-PDE11), PDE1, PDE3, PDE4, and PDE5 are the predominant enzyme families expressed in vascular myocytes, with PDE3 and PDE4 accounting for the majority of the cAMP-hydrolyzing activity (Polson and Strada, 1996;Maurice et al, 2003). Rolipram, a selective PDE4 inhibitor (Ahmad et al, 2015), robustly activated Kv7 currents in A7r5 cells (Fig. 3) but not in MASMCs (Fig.…”

Кавинтон (Винпоцетин): Новые Возможности Клинического Применения

“…Áîëåå òîãî, îíè ÿâëÿþòñÿ ìèøåíüþ äëÿ ñîåäèíåíèé, âîññòàíàâëèâàþ-ùèõ êîãíèòèâíûå ïðîöåññû [28,66], îñëàáëÿþùèõ ïðîÿâëåíèÿ çàáîëåâàíèé äûõàòåëüíûõ ïóòåé, áîëåçíè Ïàðêèíñîíà è áîëåçíè Õàíòèíãòîíà [61], óìåíüøàþ-ùèõ ãèïåðòðîôèþ ìèîêàðäà, ýðåêòèëüíóþ äèñôóíê-öèþ, ëåãî÷íóþ ãèïåðòåíçèþ [7,35]. Ñåìåéñòâî ÔÄÝ íàñ÷èòûâàåò 11 ôîðì, ïðè÷åì èõ äåëÿò íà íåñêîëüêî ãðóïï â çàâèñèìîñòè îò ñóáñòðàòíîé ñïåöèôè÷íîñòè.…”

Pharmacological targeting of AKAP-directed compartmentalized cAMP signalling

“…Phosphodiesterases (PDEs) hydrolyse cAMP to 5'AMP. Depending on their intracellular location they establish cAMP gradients throughout the cells and thereby cAMP microdomains [10,11]. Thus both PDEs and AKAPs define compartments and limit PKA activity.…”