Molecular mechanisms of detrusor and corporal myocyte contraction: identifying targets for pharmacotherapy of bladder and erectile dysfunction

Abstract

The Post-Genomic age presents many new challenges and opportunities for the improved understanding, diagnosis and treatment of human disease. The long-term goal is to identify molecular correlates of disease processes, and use this information to develop novel and more effective therapeutics. A major hurdle in this regard is ensuring that the molecular targets of interest are indeed relevant to the physiology and/or pathophysiology of the processes being studied, and, moreover, to determine if they are specific to the tissue/organ being investigated. As a first step in this direction, we have reviewed the literature pertaining to bladder and erectile physiology/pharmacology and dysfunction and attempted to summarize some of the critical molecular mechanisms regulating detrusor and corporal myocyte tone. Because of the vast amount of published data, we have limited the scope of this review to consideration of the calcium-mobilizing and calcium-sensitizing pathways in these cells. Despite obvious differences in phenotypic characteristics of the detrusor and corporal myocyte, there are some common molecular changes that may contribute to, for example, the increased myocyte contractility characteristic of bladder and erectile dysfunction (i.e. increased Rho kinase activity and decreased K(+) channel function). Of course, there are also some important distinctions in the pathways that modulate contractility in these two cell types (i.e. the contribution of ryanodine-sensitive calcium stores and the nitric oxide/cGMP pathways). This report highlights some of these similarities and distinctions in the hope that it will encourage scientific discourse and research activity in this area, eventually leading to an improved quality of life for those millions of individuals that are afflicted with bladder and erectile dysfunction.

Figure 1

Schematic depiction of the physiological/pharmacological basis for contraction and relaxation of corporal myocytes. Mechanisms are summarized from the text and cited literature throughout this report. Where SR: sarcoplasmic reticulum, PLC: phospholiapse C, DAG: diacylglycerol, PKC: protein kinase C, IP₃: inositol trisphosphate, MLC: myosin light chain. Stimulatory pathways are illustrated via the green arrows, while the red arrows represent inhibitory regulation.

Figure 2

Schematic depiction of the major regulatory mechanisms that modulate detrusor myocyte tone. Where: denotes a negative or inhibitory effect, although clearly there are several types of K channels known to be present in detrusor myocytes, SR: sarcoplasmic reticulum, RyR: ryanodine receptor, PLC: phospholiapse C, DAG: diacylglycerol, PKC: protein kinase C, IP₃: inositol trisphosphate, MLC: myosin light chain, CICR: calcium-induced calcium release, A: agonist, R: receptor. Stimulatory pathways are illustrated via the green arrows, while the red arrows represent inhibitory regulation. Again, mechanisms are summarized from the text and relevant cited literature. Note that nothing is implied by the location and stoichiometry of the depicted potassium and calcium channel, which are merely representative of their presence and physiological/pharmacological importance. A more accurate depiction of their location relative to the SR calcium stores is shown in Figure 3.

Figure 3

Detailed depiction of the known calcium mobilizing mechanisms in detrusor myocyte tone. This diagram highlights the multiple points in these processes in which molecular changes have been correlated with alterations in detrusor myocyte function, as summarized in the text.

Figure 4

Illustration of some similarities and distinctions in molecular regulation of detrusor and corporal myocyte tone. In this diagram, targets that are apparently more important to the regulation of the detrusor myocyte are shown in red (RyR receptor and SERCA), while those thought to be more important to the regulation of corporal smooth muscle are shown in yellow (PDEV/cGMP/nitric oxide pathway). If a target is important to both cell types, then it appears orange (BK_Ca, L-type calcium channel, gap junctions, Rho Kinase). Such observations may point the way to novel therapeutic possibilities.