Overactive bladder is a debilitating disorder characterized by increased urinary frequency, urgency or incontinence. In the US, overactive bladder is a more common chronic condition than diabetes or peptic ulcer, yet, for most cases, the etiology of overactive bladder remains unknown.
The aim of current pharmacologic treatment of overactive bladder has fallen short of its target to selectively reduce involuntary activity of detrusor smooth muscle (DSM) without affecting other organs, and to reduce detrusor contractions during bladder filling, and not during voiding. The discovery of novel pharmacological agents for the treatment of overactive bladder awaits the identification of regulatory mechanisms specific to DSM contraction. The long-term goal of my laboratory is to precisely identify the subcellular mechanisms that regulate DSM contractile protein activation, and to identify therapeutic agents to treat urinary conditions such as overactive bladder. Smooth muscle contractions occur when stimuli elevate [Ca2+]i. However, recent studies demonstrate that increased sensitivity of contractile proteins to Ca2+ represents an equally important regulatory mechanism. The recent discovery that overactivity of vascular smooth muscle Ca2+-sensitization is involved in the pathophysiology of hypertension has provided the impetus to study and understand the physiology of Ca2+-sensitization in all smooth muscle types. This discovery also raises the possibility that overactive Ca2+-sensitization contributes to overactive bladder.
Aim 1 will test the hypothesis that Ca2+-sensitivity plays an essential role in regulation of OSM contractions. Whether RhoA kinase, phospholipase A2-generated arachidonic acid or extracellular signal-regulated kinase (ERK)-activated caldesmon phosphorylation, participate in Ca2+-sensitization-induced contractions will be tested, and the specific role M2 receptors play in this pathway will be determined.
Aim 2 will test the hypothesis that detrusor-stretch and beta adrenergic receptor stimulation relax DSM by activating cAMP-dependent protein kinase, which reduces [Ca2+]i and Ca2+-sensitivity. The degree to which telokin phosphorylation, inactivation of RhoA, and reductions in ERK-induced caldesmon phosphorylation participate in reduced Ca2+-sensitivity will be elucidated. Collectively, these studies will provide new insights into the cellular mechanisms regulating DSM contractions.
