Physiological Roles for K posative Channels and Gap Junctions in Urogenital Smooth Muscle Implications for Improved Understanding of Urogenital Function, Disease and Therapy

Abstract

Smooth muscle cells constitute a heterogeneous collection of effector cells that, by virtue of both their constituency in blood vessels and presence as primary parenchymal cells in diverse tissues, affect the function of all organs. Thus, perhaps it is not surprising that alterations in, and/or dysfunction of, smooth muscle cells are quite common, and responsible, at least in part, for the morbidity and mortality associated with a very wide range of human diseases. These facts point to the necessity for improved understanding of the mechanism(s) governing the control of myocyte contractility (i.e., tone). Such understanding has been rapidly forthcoming in recent years, and has indicated that in many smooth muscle cell types intercellular communication through gap junctions acts in concert with nonjunctional (K+) ion channels to make important contributions to the control of myocyte tone and tissue homeostasis in physiologically diverse organs. Intercellular communication through connexin43-derived gap junction channels and K+ flux through the KCa and KATP channel subtypes, in particular, appear to play prominent roles in this process. The goal of this report, therefore, is to review the data concerning junctional and nonjunctional ion channels on the detrusor myocytes of the urinary bladder, as well as on the specialized vascular myocytes of the corpus cavernosum. The choice of an excitable (i.e., bladder detrusor myocytes) and nonexcitable (i.e., corporal smooth muscle) smooth muscle cell type ensures that the discussion will at least encompass consideration of a large portion of the spectrum of physiological possibilities for the participation of junctional and nonjunctional ion channels in the initiation, maintenance and modulation of smooth muscle tone. A central thesis of this communication is that detailed knowledge of the myocyte- and tissue-specific properties of K+ channels and gap junctions will likely lead to the improved understanding and treatment of human smooth muscle diseases/disorders.

Increased connexin43-mediated intercellular communication in a rat model of bladder overactivity in vivo

“…Briefly, gap junction proteins, or connexins, are formed by the union, across the extracellular space, of two identical hexameric assemblies of connexin proteins. The mammalian connexin gene family now numbers 16, but thus far, connexin43 (Cx43) is the best characterized connexin identified in rat and human bladder myocytes (30). These aqueous intercellular channels provide the anatomic substrate for partial cytoplasmic continuity between adjacent cells and are freely permeable to molecules of up to Ϸ1,000 Da.…”

Gene transfer for the therapy of erectile dysfunction: progress in the 21st century

“…29 Previous reports have shown that there are at least four potassium channels present in the plasma membranes of the cells of Gene transfer for the therapy of erectile dysfunction A Melman the human corpora. [28][29][30][31][32] These channels are the…”

Frontiers in gene therapy for erectile dysfunction

“…K channels provide an important mechanism for the regulation of corporal smooth muscle cell tone, [20][21][22][23] and moreover, represent a convergence point for mediating the effects of a wide array of endogenous neurotransmitters, neuromodulators and hormones. As recently pointed out then, K channels are an attractive therapeutic target for both traditional small molecule pharmacology as well as gene-based approaches.…”

“…5,21 While the K Ca has been the primary focus of our efforts to date, unpublished data from our group also indicate that gene transfer with the a-subunit of another important K channel subtype, namely Kir6.2 (see Christ 21 for details) might also restore diminished erectile capacity in the aged rat model (Christ et al, unpublished observations). The strategy behind ion channel gene therapy is based on the tight link between K channel activity, transmembrane calcium flux through voltage-dependent calcium channels, and corporal smooth muscle cell tone (see Christ et al, 10 Karicheti and Christ, 20 Christ, 21 , Spektor et al, 22 Melman and Christ…”

“…The evidence consistent with this supposition has been recently reviewed. 10,[20][21][22][23] Of major importance to this report is the fact that the gene product, namely, the Maxi-K channel, apparently exhibits little or no activity in the corporal smooth muscle cell during flaccidity, 10,20,21 but becomes robustly activated by the endogenous erectile second messenger pathways during tumescence. Consistent with the fact that hSlo has little impact on baseline corporal smooth muscle activity, no evidence for the possibility of priapism (ie, increased resting intracavernous pressure) has been observed in our preclinical work.…”