Smooth muscle signalling pathways in health and disease

Abstract

Smooth muscle contractile activity is a major regulator of function of the vascular system, respiratory system, gastrointestinal system and the genitourinary systems. Malfunction of contractility in these systems leads to a host of clinical disorders, and yet, we still have major gaps in our understanding of the molecular mechanisms by which contractility of the differentiated smooth muscle cell is regulated. This review will summarize recent advances in the molecular understanding of the regulation of smooth muscle myosin activity via phosphorylation/dephosphorylation of myosin, the regulation of the accessibility of actin to myosin via the actin-binding proteins calponin and caldesmon, and the remodelling of the actin cytoskeleton. Understanding of the molecular 'players' should identify target molecules that could point the way to novel drug discovery programs for the treatment of smooth muscle disorders such as cardiovascular disease, asthma, functional bowel disease and pre-term labour.

Figure 1

Pathways that regulate contractility (demonstrated and putative).

Figure 2

Regulatory pathways leading to myosin light chain phosphatase inhibition and activation. Activating signalling molecules (leading to relaxation) are shown in green, inhibitory molecules (supporting contractility) are shown in pink. Molecules shown in blue are bimodal and can be both, an inhibitor or an activator.

Figure 3

Domain structure of CaMKII. The phos-phosites are indicated with ‘P’ on top of the amino acid residues. The numbering is according to the a-isoform.

Figure 4

Domain structure of calponin (CaP). CaP proteins consist of a conserved N-terminus including the CH-domain (blue), the Tnl-like domain (yellow) as well as the three C-terminal repeats (green). However, the very C-terminal end is a highly variable region (red) that differs in size and amino acid sequence within the three CaP isoforms.

Figure 5

Model of bCaP function in regulation of smooth muscle cell contractility. (1) Starting with a yet unidentified stimulus, PKC-α/ɛ gets subsequently activated, an event that is further supported by bCaP binding. PKC-α/ɛ may now phosphorylate bCaP, leading to an impaired actin-binding property of bCaP (2) Hence the ERK1/2-PKC-a/e-bCaP complex translocates to the cell cortex where it binds to SmAV, a protein acting as a scaffold for Raf and MEK. Moreover the PKC-α/ɛ molecule gets fully activated by membrane bound diacylglycerol that is produced by activated phospholipase C coupled to GPCR. The activated PKC-α/ɛ molecule phosphorylates Raf, which in turn phosphorylates MEK that now activates ERK1/2. Whereas the SmAV-bCaP-PKC-α/ɛ complex stays at the membrane, (4) activated ERK1/2 moves back to the actin filaments where it comes in contact with its substrate h-CaD. Phosphorylation of the h-CaD molecule leads to its conformational change, resulting in enabled actin-myosin interaction and hence to contraction. For detailed information see text/article.

Figure 6

Cytoskeletal remodelling at focal adhesions and regulation of smooth muscle contraction. Integrins connect the extracellular matrix to actin filaments within the cell. Actin filaments are linked to cytoplasmic domain of integrin by linker proteins (green). Mechanical and/or contractile stimuli induce the cytoskeletal remodelling by recruiting signalling proteins (orange) to focal adhesions.