# ACTIN BASED REGULATION OF SMOOTH MUSCLE CONTRACTION

> **NIH NIH R01** · EAST CAROLINA UNIVERSITY · 1989 · $59,770

## Abstract

An understanding of the mechanism of force production in smooth
muscle and its regulation is essential in dealing with the very
serious disorders associated with smooth muscle such as vascular
disease.  When fully understood, the differences between smooth
and skeletal muscles can be exploited therapeutically to combat
these disorders.  Smooth muscle generates more tension per
myosin molecule than does skeletal muscle.  Smooth muscle can
also maintain tension for long periods of time after stimulation
(latch).  These differences are probably due to differences in the
subcellular organization, the structure of myosin, and the
regulatory systems.  The regulatory systems are of particular
medical importance since only they can be modulated by an
external influence.  A particularly interesting component of the
regulatory system of smooth muscle is the actin and calmodulin
binding protein caldesmon.

Caldesmon inhibits the actin activated hydrolysis of ATP by
smooth and skeletal myosin and their proteolytic subfragments.
The inhibition of the ATPase activity of skeletal myosin
subfragment-1 is associated with an inhibition of the binding of
subfragment-1 to actin.  In contrast, the ATPase activity of heavy
meromyosin from smooth muscle occurs with an increase in the
binding of heavy meroymosin to actin.  The present proposal is to
determine how caldesmon can have opposite effects on binding
and still produce inhibition of ATPase activity.  In so doing the
mechanism of caldesmon activity will be clarified and further
differences between smooth and skeletal myosins will be explored.
Three hypotheses for the increased binding of smooth heavy
meromyosin in the presence of ATP will be explored:  (1) The
presence of two binding sites on actin-caldesmon - one productive
and the other nonproductive.  (2) The reduction in the rate of ADP
release.  (3) A calcium dependent crosslinking of the actin
filaments.  These studies will involve measurement of binding of
caldesmon and myosin subfragments to actin, steady-state
kinetics, rapid kinetic measurements using a stopped-flow
spectrophotometer, chemically crosslinking actin, myosin and
caldesmon, proteolytic digestion of various protein-protein
complexes to determine sites of interaction, and affinity
chromatography.  Additional studies are designed to determine
the role of uncharacterized caldesmon binding proteins in the
regulatory process.  Also, the mechanism of reversal of
caldesmon's inhibitory activity will be investigated.

## Key facts

- **NIH application ID:** 3157110
- **Project number:** 5R01AR035216-05
- **Recipient organization:** EAST CAROLINA UNIVERSITY
- **SAM.gov UEI:** HWPEKM8VFTJ9
- **Principal Investigator:** JOSEPH M CHALOVICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $59,770
- **Award type:** 5
- **Project period:** 1985-04-01 → 1993-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3157110

## Citation

> US National Institutes of Health, RePORTER application 3157110, ACTIN BASED REGULATION OF SMOOTH MUSCLE CONTRACTION (5R01AR035216-05). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3157110. Licensed CC0.

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