Hydrolysis muscle physiology

Nonmuscle/smooth muscle myosins-Il are structurally similar to striated muscle myosin-II, but they have slower rates of ATP hydrolysis than do their striated muscle counterparts. Nonmuscle/smooth muscle myosin-II is also regulated differently than striated muscle myosin-II. Nonmuscle myosin-II is divided into the invertebrate and vertebrate branches (Cheney et al., 1993). This group is ubiquitous because it is present in most lower organisms, such as slime molds, amoeba, sea urchins, etc., and in virtually all mammalian nonmuscle cells. Smooth muscle myosin-II is also somewhat heterogeneous in that at least three separate forms of smooth muscle heavy chains, with molecular weights of 196,000, 200,000, and 204,000 have been identified (Kawamoto and Adelstein, 1987). The physiological properties of these separate myosin heavy chains are not yet known. 

The regulation of smooth muscle and nonmuscle myosin-II is substantially different from the mechanism described above for two important reasons. First, there is no troponin in smooth muscle and nonmuscle cells. Second, although the rate of hydrolysis of ATP by these myosins is low in the presence of physiological concentrations of Mg % the addition of actin does not necessarily result in the stimulation of ATP hydrolysis by smooth muscle or nonmuscle myosin-II. These observations suggest the presence of a unique mechanism for Ca " regulation in smooth and nonmuscle cells, and that these myosins require an activation process before actin can stimulate ATP hydrolysis. 

Actin, the major constituent of the thin filaments, exists in two forms. In solutions of low ionic strength it exists as a 42kDa monomer, termed G-actin because of its globular shape. As the ionic strength of the solution rises to that at the physiological level, G-actin polymerizes into a fibrous form, F-actin, that resembles the thin filaments found in muscle. Although actin, like myosin, is an ATPase, the hydrolysis of ATP is not involved in the contraction-relaxation cycle of muscle but rather in the assembly and disassembly of the actin filament. 

The initial high levels of IP3 in response to agonist-receptor interaction are not maintained during the sustained phase of contraction (Chilvers et al, 1989 Chilvers and Nahorski, 1990). IP3 fells to baseline levels within a minute of the onset of contraction. I(1,4,5)P3 is metabohzed by two pathways, both of which are activated by increases in cytosolic Ca " hydrolysis by a 5-phosphatase enzyme to I(1,4)P2, or phosphorylation to I(1,3,4,5)P4 and subsequent hydrolysis to its inactive isomer I(1,3,4)P3 (Chilvers and Nahorski, 1990). No physiological role for I(1,3,4,5)P4 has yet been identified in airway smooth muscle, although in other cells evidence exists that I(1,3,4,5)P4 may modulate plas-malemmal Ca ion channels (Irvine and Moor, 1986). The only phosphoinositide metabolite which has been shown to release stored Ca in ASM is I(1,4,5)P3. 

The physiological activity of acetylcholine relies on local release, stimulation of the receptor, then rapid hydrolysis (deacetylation) by acetylcholinesterase, which results in deactivation. The indole alkaloid physostigmine, from the West African calabar bean, and the relatively simple synthetic compound pyridostigmine, which has a more obvious relationship to choline, are reversible inhibitors of acetylcholinesterase. Controlled inhibition of the enzyme by such drugs, which results in a build-up of ACh, is useful in conditions such as myasthenia gravis, a muscle weakness, which is caused by insufficient production of ACh. 

The magnitudes of entropies of activation have provided valuable information regarding the details of the interactions between enzymes and substrates. The process of muscular contraction involves an interaction between the muscle enzyme myosin and adenosine triphosphate (ATP). Myosin is an enzyme which catalyzes the hydrolysis of ATP, a process which we have seen (p. 246) to be more exergonic than is the case for many other phosphates, and this hydrolysis contributes energy for contraction. Because of its catalytic action, myosin is also referred to as adenosine triphosphatase (ATP-ase). When the activated complex is formed from ATP ase and its substrate ATP, the entropy of activation is about 41 cal K" mol under approximately normal physiological conditions. We saw on p. 400, on the basis of a very simple electrostatic theory of AS values for ionic reactions in aqueous solution, that there will be a positive contribution of about 10 cal mol for each unit of the product [ [ % ( The long myosin molecules bear a series of positive... 

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