Phosphodiesterase Inhibition as a Mechanism of Ion Channel Modulation by Celecoxib

The overall objective of this thesis work is to determine the mechanism by which celecoxib modulates Kv7 potassium channels in vascular smooth muscle cells. The central hypothesis of the project is that celecoxib modulates Kv7 potassium channels in vascular smooth muscle cells through inhibition of phosphodiesterase 4 (PDE4, which catalyzes the breakdown of cyclic adenosine monophosphate (cAMP)), thereby activating a cAMP/protein kinase A (PKA) signaling pathway. The aims of this thesis targeted different points in the cAMP/PKA pathway with pharmacological interventions using whole cell perforated patch clamp electrophysiology and biochemical methods. The data suggest multiple mechanisms by which celecoxib could be eliciting its Kv7 channel activation with better evidence suggesting requirement of a critical residue for channel activation than an indirect PDE4/cAMP/PKA-dependent pathway. Further work is needed to determine celecoxib’s exact mechanism of Kv7 channel activation