The force is with α‐actinin: dynamic regulation of the extracellular matrix‐cytoskeletal connection in airway smooth muscle

Smooth muscle is a diverse tissue involved in a broad range of physiological processes, from blood pressure regulation to childbirth. Its purpose in life is to contract or relax in response to appropriate stimuli. Contractile stimuli usually elicit an increase in cytosolic free [Ca2+], leading to myosin light chain phosphorylation and contraction, thereby regulating the calibre of the blood vessel or the shape and volume of the uterus, for example (Somlyo & Somlyo, 1994). Contraction is believed to occur via an actomyosin cross-bridge cycling (or better, swinging lever-arm)/sliding filament mechanism, as in cardiac and skeletal muscles (Holmes, 1997). Smooth muscle, however, appears to be a more ‘plastic’ tissue than striated muscles, consistent with the need to adapt within seconds to variations in external forces (Gunst et al. 1995; Seow, 2005). This plasticity appears to include the reversible association of actin filaments with adhesion junctions within the sarcolemma (plasma membrane). These structures contain transmembrane integrins associated with extracellular matrix proteins on the outside and cytoskeletal proteins on the inside, and thereby permit tension transmission between the contractile machinery and the extracellular matrix (Mehta & Gunst, 1999). The structural organization of the smooth muscle cytoskeleton appears to be far more labile than was once thought, with tension generation involving dynamic cytoskeletal processes that occur as cross-bridge cycling is activated. For example, polymerization of a small proportion of cellular actin may be required for force generation, and the recruitment of cytoskeletal proteins to adhesion junctions within the sarcolemma appears necessary to strengthen connections between actin filaments and the extracellular matrix. These connections support the transmission of force generated by the contractile machinery (Mehta & Gunst, 1999; Herrera et al. 2004). Previous work from Susan Gunst's laboratory has provided important insights into the dynamic aspects of adhesion junctions, e.g. the translocation of proteins such as paxillin and vinculin, which serve to anchor actin filaments to these sites within the plasma membrane (Opazo Saez et al. 2004). In this issue of The Journal of Physiology, Zhang & Gunst (2006) focus on another cytoskeletal protein, α-actinin, an actin- and integrin-binding protein that is localized in cytoplasmic dense bodies and sarcolemmal dense plaques of smooth muscle cells (Fay et al. 1983). The authors reach the tantalizing conclusion that the recruitment of α-actinin to integrin complexes is necessary for tension development in tracheal smooth muscle tissue. Zhang and Gunst have exploited knowledge of the domain structure and binding properties of α-actinin to test the hypothesis that contractile stimulation of airway smooth muscle induces translocation of α-actinin from the cytosol to the sarcolemma, where it connects β-integrin to actin filaments. Both intact tracheal tissue and freshly isolated tracheal smooth muscle cells were utilized. Treatment with the contractile agonist acetylcholine induced translocation of α-actinin from the cytosol to the sarcolemma (as shown by confocal immunofluorescence microscopy) and increased the amount of β1-integrin that coimmunoprecipitated with α-actinin. Importantly, the translocation, which preceded contraction, was reversible following removal of the stimulus and was not stimulus-specific since it was also observed with histamine. Expression of a green fluorescent protein–α-actinin fusion protein confirmed, in real time using laser-scanning confocal microscopy, that α-actinin translocates to the membrane in response to acetylcholine. In a particularly elegant approach, expression of the central rod domain of α-actinin (which binds to β-integrins but not actin) inhibited this translocation and the association of α-actinin with β1-integrin and, most importantly, inhibited contraction without affecting myosin phosphorylation or actin polymerization. It did not, however, affect the translocation of paxillin, vinculin or talin. Electron microscopy of tissues expressing the rod domain of α-actinin or the full-length protein revealed no differences in cell morphology or overall cytoskeletal organization compared to untreated tissue. It is interesting that the rod domain of α-actinin associates with the plasma membrane even in the unstimulated cell, suggesting that it may have a conformation similar to that of full-length α-actinin after acetylcholine stimulation, with an exposed β-integrin-binding site. These provocative findings will help to focus more attention on the dynamics of adhesion complexes in smooth muscle and raise a number of intriguing questions. Is this a general phenomenon common to all smooth muscle cell types? Does it occur in response to all physiological contractile stimuli or only a subset, e.g. activation of specific receptors? What are the molecular mechanisms that trigger and direct the translocation of α-actinin to adhesion junctions? Are phosphoinositides involved, as suggested by the authors, based on recent work with fibroblasts (Fraley et al. 2005)? What causes the dissociation of α-actinin from β1-integrin following removal of the contractile stimulus? What is the source of the ‘translocatable’α-actinin: cytoplasmic dense bodies? Is the extent of translocation of α-actinin proportional to the intensity of the stimulus? If so, could such cytoskeletal reorganization be a key element in grading active force development, in which case cytoskeletal reorganization may be considered the ‘third rail’ of smooth muscle contraction alongside Ca2+-dependent events and myofilament Ca2+ sensitization? There has never been a shortage of exciting new avenues to explore in the smooth muscle field. This paper illustrates an emerging area related to smooth muscle function that deserves greater attention, not least due to its potential importance to smooth muscle physiology and pathophysiology.

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