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Journal of Physiology (2001), 537.2, pp. 329
© Copyright 2001 The Physiological Society
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The development of the latch hypothesis as a component of smooth muscle contractile regulation has fostered intense research in the past 20 years. The original paper proposing latch (Dillon et al. 1981) has generated more than 500 citations, testing possible mechanisms both in support and opposition. There is general consensus that phosphorylation of the regulatory (20 kDa) light chain of myosin is a sufficient step for the activation of smooth muscle. The mechanical changes associated with smooth muscle contraction, particularly the decline in velocity during prolonged activation, have been demonstrated by many laboratories and are generally accepted. Key elements, especially how that slowing occurs and the degree to which thin filament controls modulate contraction, remain to be solved.
The latch hypothesis is attractive because it addresses a physiological property of tonic smooth muscles that must exist. Large blood vessels must remain contracted from approximately 5 weeks into gestation until death in order to maintain blood pressure. The energy cost of maintaining contraction using short duty cycle actin-myosin interactions is prohibitive. The dephosphorylation of the light chains while myosin heads are attached to actin provides an attractive potential mechanism for contractile maintenance that remains valid.
The latch hypothesis is less important as a regulatory tool for phasic smooth muscle. Prolonged contractile maintenance of uterine or digestive smooth muscles, for example, would not be beneficial. Thus, there must exist in phasic smooth muscles mechanisms that either limit, replace or modulate significantly the mechanical properties so important to tonic smooth muscles.
The methods involved in trying to ascertain the regulation of smooth muscle contraction have been myriad, and clever innovations using molecular genetics, motility assays, isolated single cells, tissue culture, membrane disruptions and antisense oligonucleotides have generated a wealth of data on the contractile and regulatory components of smooth muscle. A continuing difficulty, however, is the alteration in smooth muscle activity associated with virtually all deconstructions. Changing the state of the tissue usually results in mechanical events that do not occur in vivo. Proposed regulatory schemes based on experiments from fragments of smooth muscle have not generated any consensus on contraction modulation. In some cases seemingly identical experiments have produced contradictory results.
In a paper in this issue of The Journal of Physiology describing experiments using intact tissues, Je et al. (2001) propose that the phosphorylation of calponin causes the removal of inhibition of contractile proteins and an increase in contractility, and may play a role in the generation of latch. Further experiments by different laboratories will test the validity of this model. Other technologies, such as methods for determining actin-myosin binding angles in the phosphorylated and unphosphorylated states, will also generate mechanisms confirming, modifying or rejecting current models of smooth muscle regulation. In any case, what are the limitations on the models produced to enhance our understanding of smooth muscle contraction?
Any model system has to address the mechanics, ATPase activity, metabolic environment and structure of smooth muscle. The mechanics of muscle make it different from all other tissues. Any proposed regulatory system has to explain the temporal changes that occur in smooth muscle activation and the amount of force generated by different smooth muscle types. Any modulatory system not involving calcium has to co-exist with the calcium activation of myosin light chain kinase (MLCK) or demonstrate conclusively that the system is calcium independent.
All systems have to be compatible with the regulation of the myosin ATPase. There are no other accepted ATP-utilizing sites in smooth muscle producing force generation and shortening. Proposed systems must either be part of the kinase/phosphatase regulation of the ATPase, or successfully circumvent it. There is general acceptance of MLCK regulatory activity and the growth of phosphatase regulation as an area of research may supply fertile ground for additional signal-regulation controls (Somlyo & Somlyo, 2000).
Any modulatory plan must work in the cellular metabolic environment. There is a wealth of papers that show changes in parts of the contractile system using unphysiological metabolite concentrations. It is the burden of any proposal to show that a system that works in unphysiological conditions, such as altered pH, ionic strength, ATP/ADP/phosphate levels, etc., has validity under cellular conditions (Dillon, 2000). Also, changes in the concentration of a control substance must be of sufficient magnitude and within the physiological range for the system to exist in vivo.
Recent advances in our understanding of the structure of smooth muscle must be considered. Localization of regulatory proteins, such as MLCK on F-actin, will limit access of substrate to enzyme under some conditions. Smooth muscle cannot be treated as a bag of proteins and metabolites, but rather as sets of complementary molecules. Interactions between molecules limit the degrees of freedom available, providing temporal and energetic stability at the cost of systemic restrictions (Root-Bernstein & Dillon, 1997).
The application and understanding of these limitations will lead to a complete view of the activation and modulation of smooth muscle contraction. Merging individual experiments with basic physiological principles maximizes the prospect of increasing our knowledge and understanding. By placing their research data in a unifying overall context, Je et al. have taken an appropriate step in this direction.
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REFERENCES |
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| DILLON, P. F. (2000). Journal of Vascular Research 37, 532-539 | [Medline] |
| DILLON, P. F., AKSOY, M. O., DRISKA, S. P. & MURPHY, R. A. (1981). Science 211, 495-497 | |
| JE, H.-D., GANGOPADHYAY, S. S., ASHWORTH, T. D. & MORGAN, K. G. (2001). Journal of Physiology 537, 567-577 | [Abstract/Full Text] |
| ROOT-BERNSTEIN, R. S. & DILLON, P. F. (1997). Journal of Theoretical Biology 188, 447-479 | [Medline] |
| SOMLYO, A. P. & SOMLYO, A. V. (2000). Journal of Physiology 522, 177-185 | [Abstract/Full Text] |
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