The physiology, pathophysiology and therapeutic potential of gap junctions in smooth muscle

Phenotypic variability in smooth muscle cells accounts, in large part, for the incredible functional diversity required of the involuntary hollow organs of the body (i.e., respiratory passages, blood vessels, gastrointestinal tract, urogenital tract, etc.). In all instances coordination of smooth muscle cell responses, that is, contraction and relaxation, is critical to normal organ function. While numerous biological mechanisms exist for coordinating smooth muscle cell responses, intercellular communication through gap junctions represents a common denominator present in all organ systems. In this report, we review the evidence documenting the presence and functional significance of myocyte gap junctions to physiologically distinct organ systems, and furthermore, provide some examples of their putative roles in organ pathology. Finally, we advance the thesis that despite their ubiquity and heterogeneous expression, gap junctions are nonetheless potentially attractive therapeutic targets for the treatment of certain smooth muscle disorders. Their therapeutic efficacy will necessarily hinge on the existence of connexin isoform-selective junctional effects. The overall rationale for targeting the intercellular pathway is therefore analogous to strategies that target other ubiquitously expressed ion channels, such as calcium or potassium channels. Such strategies have proved efficacious for the treatment of a wide range of human smooth muscle disorders including hypertension, urinary incontinence and sexual function.