Actin cytoskeletal dynamics in smooth muscle: a new paradigm for the regulation of smooth muscle contraction

Abstract

A growing body of data supports a view of the actin cytoskeleton of smooth muscle cells as a dynamic structure that plays an integral role in regulating the development of mechanical tension and the material properties of smooth muscle tissues. The increase in the proportion of filamentous actin that occurs in response to the stimulation of smooth muscle cells and the essential role of stimulus-induced actin polymerization and cytoskeletal dynamics in the generation of mechanical tension has been convincingly documented in many smooth muscle tissues and cells using a wide variety of experimental approaches. Most of the evidence suggests that the functional role of actin polymerization during contraction is distinct and separately regulated from the actomyosin cross-bridge cycling process. The molecular basis for the regulation of actin polymerization and its physiological roles may vary in diverse types of smooth muscle cells and tissues. However, current evidence supports a model for smooth muscle contraction in which contractile stimulation initiates the assembly of cytoskeletal/extracellular matrix adhesion complex proteins at the membrane, and proteins within this complex orchestrate the polymerization and organization of a submembranous network of actin filaments. This cytoskeletal network may serve to strengthen the membrane for the transmission of force generated by the contractile apparatus to the extracellular matrix, and to enable the adaptation of smooth muscle cells to mechanical stresses. Better understanding of the physiological function of these dynamic cytoskeletal processes in smooth muscle may provide important insights into the physiological regulation of smooth muscle tissues.

Fig. 1.

Signals activated by integrin receptors and G protein-coupled receptors (GPCR) collaborate to regulate actin cytoskeletal remodeling and activation of the actomyosin system in smooth muscle. These two processes can be activated independently of one another, but the development of contractile tension requires the activation of both the actomyosin system and actin polymerization.

Fig. 2.

Molecular organization of integrin/cytoskeletal adhesion junctions in smooth muscle. Actin filaments are linked to integrin proteins via actin cross-linking proteins that bind to the cytoplasmic tails of integrin proteins. Scaffolding proteins regulate the assembly of protein complexes at adhesion junctions in response to contractile stimulation. Proteins that assemble into macromolecular complexes at adhesion junctions regulate actin polymerization. HSP, heat shock protein; ILK, integrin-linked kinase; FAK, focal adhesion kinase; N-WASp, neuronal Wiskott-Aldrich syndrome protein.

Fig. 3.

Signaling pathway for the regulation of actin polymerization in smooth muscle. ECM, extracellular matrix.

Fig. 4.

Integrated model for function of cytoskeletal dynamics in smooth muscle contraction. The activation of the smooth muscle cell stimulates the assembly of macromolecular protein complexes at cell membrane/ECM adhesion junctions that regulate the formation of a subcortical network of actin filaments and fortify connections between the actin filaments and integrin proteins. The formation of a subcortical actin filament network strengthens the membrane for the transmission of force generated by the actomyosin system and enables adaptation of the smooth muscle cell to external forces.