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This issue of the Journal of Applied Physiology introduces a new Highlighted Topics series, "Signal Transduction in Smooth Muscle." The mechanisms by which smooth muscle cells transduce external stimuli (e.g., pharmacological and mechanical) into functional responses have been the subject of investigation by many laboratories for decades. An understanding of these molecular processes is integral to the elucidation of the basic physiological function of many organs and tissues and to the development of therapeutic interventions for many common pathological conditions, such as asthma and hypertension.

For many years, it has been recognized that an elevation in intracellular calcium concentration ([Ca²⁺]_i) initiates a signaling cascade that involves calmodulin, Ca²⁺/calmodulin-dependent activation of myosin light-chain kinase, and phosphorylation of the regulatory (20-kDa) myosin light chain (rMLC). The initial step in the signal transduction of smooth muscle cells is the elevation of [Ca²⁺]_i. In this Highlighted Topics series, invited mini-reviews will focus on recent advances in our understanding of this traditional signaling pathway, as well as other, more novel signaling mechanisms that have been recently elaborated. The elevation of [Ca²⁺]_i in smooth muscle cells may involve complex transduction mechanisms that can vary from one smooth muscle type to another. With the development of more advanced imaging techniques to measure [Ca²⁺]_i (e.g., real-time confocal microscopy), it has become apparent that there are localized [Ca²⁺]_i transients (e.g., Ca²⁺ sparks and propagating Ca²⁺ waves). Advances in our understanding of Ca²⁺ signaling will be addressed by Drs. Christina Pabelick, Gary Sieck, and Y. S. Prakash in a review entitled "Significance of spatial and temporal heterogeneity of calcium transients in smooth muscle" and also in a review by Dr. Kent Sanders entitled "Mechanisms of calcium handling by smooth muscle."

Moving down the signaling cascade, Dr. Gabriele Pfitzer will explore the complex network of activating and inhibiting cellular signals that regulate the rMLC phosphorylation in a mini-review entitled "Regulation of myosin phosphorylation in smooth muscle." She will address the relationships between [Ca²⁺]_i, rMLC phosphorylation, and contraction in smooth muscle. It is now recognized that signals from multiple pathways converge to modulate the sensitivity of rMLC phosphorylation to changes in [Ca²⁺]_i by directly regulating the activity of the Ca²⁺/calmodulin-dependent myosin light-chain kinase as well as by regulating the activity of myosin type I phosphatase, which mediates the dephosphorylation of the rMLC.

The role of thin filament proteins in the regulation of cross-bridge cycling in smooth muscle activity has been a source of controversy for a number of years. In a mini-review by Drs. Kathleen Morgan and Samudra Gangopadhyay entitled "Cross-bridge regulation by thin filament associated proteins," current concepts of the identity and possible functions of the actin binding proteins caldesmon, calponin, tropomyosin, and SM22 in the regulation of cross-bridge activity in smooth muscle will be addressed. The function of some of these proteins may take on increased importance under specific physiological or pathophysiological conditions. For example, caldesmon may play a critical role in the suppression of uterine contractility during pregnancy.

Smooth muscle cells employ multiple mechanisms to adapt and respond to changes in their external physical environment. Acute changes in cytoskeletal structure and organization may enable the smooth muscle of hollow organs to adapt rapidly to acute changes in volume. The signaling pathways that mediate these adaptive responses of the cytoskeleton appear to be closely integrated with those that regulate gene and protein expression, suggesting that the immediate adaptive responses of smooth muscle cells may precede or initiate longer term modifications to cell phenotype and tissue structure. Integrin-mediated signaling pathways have been implicated as regulators of mechanosensitive changes in contractile protein activation and cytoskeletal organization. In a mini-review entitled "Arteriolar smooth muscle mechanotransduction: Ca²⁺ signaling pathways underlying myogenic activity," the mechanisms by which the pressure stimulus of arteriolar smooth muscle is coupled to Ca²⁺ delivery and the regulation of the contractile system in arteriolar smooth muscle will be reviewed by Dr. Michael Hill and colleagues. In addition, Drs. William Gerthoffer and Susan Gunst will explore the role of actin remodeling and cytoskeletal reorganization in the regulation of smooth muscle contractility in a mini-review entitled "Signaling to the actin cytoskeleton." They will also survey recent evidence for the role of integrin-mediated signaling pathways in the regulation of cytoskeletal dynamics and contractile protein activation as well as the role of small heat shock proteins.

There is evidence that some mediators of smooth muscle contraction and relaxation also initiate signaling pathways that regulate smooth muscle tissue structure through the modulation of cell phenotype or by regulating proliferation or hypertrophy. The elucidation of the signaling pathways involved may provide therapeutic targets for the prevention of alterations in tissue structure that are associated with some chronic diseases. For example, it is now well known that nitric oxide mediates smooth muscle relaxation through the activation of the soluble guanylate cyclase, and the elucidation of this signaling pathway has been used in recent therapeutic approaches. Drs. Thomas Lincoln, Trudy Cornwell, and Hassan Sellak will review recent information regarding the role of nitric oxide and cGMP in the regulation of vascular smooth muscle cell phenotype through the initiation of signaling pathways that regulate gene expression. Drs. Reynold Panettieri and Alaina Ammit will provide further insight into the signaling pathways mediating alterations in smooth muscle tissue structure, by discussing signal transduction pathways that regulate cell cycle events and smooth muscle cell proliferation in airway smooth muscle. Such events may offer important therapeutic targets to abrogate the airway smooth muscle hypertrophy and hyperplasia observed in the histopathology of patients with asthma and chronic obstructive pulmonary disease.

It is now clear that signal transduction in smooth muscle not only involves the regulation of contraction and relaxation but may also involve molecular pathways that regulate cell phenotype and the cell cycle and that together these pathways may be closely intertwined. In the future, studies in applied physiology will need to explore and elucidate the mechanisms by which external stimuli elicit changes in the structure and phenotypic changes of smooth muscle tissue. Knowledge of these mechanisms promises to provide important insight into the molecular basis for fundamental changes in smooth muscle structure and function that underlie several pathophysiological conditions. It is evident that future studies will need to employ an assortment of research tools, from electrophysiology to real-time imaging to molecular biology.