Inositol 1,4,5-trisphosphate smooth muscle contraction

An initial hint that Ca2+ stores are present and functional in smooth muscle cells came from earlier experiments revealing that agonist-induced contractions could be observed in the absence of extracellular Ca2+. It is now known that smooth muscle Ca2+ stores express two types of Ca2+ release channels, the ryanodine receptor (RyR) and the inositol-1,4,5-trisphosphate (L1SP3) receptor (L1SP3R) (Somlyo Somlyo 1994). Recent studies have shown that Ca2+ release from intracellular Ca2+ stores plays various important roles in the regulation of smooth muscle contraction. Local and transient releases of Ca2+ from RyR near the surface membrane, which are called Ca2+ sparks, activate Ca2+-sensitive K+... 

Most of the known actions of Ang II are mediated by the AT receptor, a Gq protein-coupled receptor. Binding of Ang II to ATi receptors in vascular smooth muscle results in activation of phospholipase C and generation of inositol trisphosphate and diacylglycerol (see Chapter 2). These events, which occur within seconds, result in smooth muscle contraction. 

GU-7, a 3-arylcoumarin derivative, has been isolated fi om Glycyrrhizae radix, which is a crude herbal medicine. GU-7 caused inhibition of platelet aggregation, phosphorylation of 40K and 20K dalton proteins, inositol 1,4,5-trisphosphate production, intraplatelet calcium increase and phosphodiesterase activity in vitro. The data indicate that GU-7 inhibits platelet aggregation by increasing intraplatelet cAMP concentration. Antiplatelet action may also explain the mechanism by which traditional medicines are effective in diabetic neuropathy [236]. Osthole causes hypotension in vivo, and inhibits platelet aggregation and smooth muscle contraction in vitro. It may interfere with calcium influx and cyclic nucleotide phosphodiesterases [12]. Cloricromene, a synthetic coumarin derivative, also possesses antithrombotic-antiplatelet activity [237]. Some of these properties of cloricromene have been attributed to the inhibition of arachidonate release from membrane phospholipids [12]. 

Sarcoplasmic reticulum (SR) is a form of the smoothfaced endoplasmic reticulum (ER) in muscles. It functions as an intracellular Ca2+ store for muscle contraction. Ca2+ is energetically sequestered into the SR by Ca2+-pump/sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA) and released via Ca2+ release channels on stimuli (ryanodine receptor in striated muscles and inositol 1,4,5-trisphosphate receptor in most smooth muscles). Endoplasmic reticulum in non-muscle tissues also functions as an intracellular Ca2+ store. 

Gilabert JA, Parekh AB 2000 Respiring mitochondria determine the pattern of activation and inactivation of the store-operated Ca2+ current Icrac- EMBO J 19 6401-6407 lino M 1990 Biphasic Ca2+ dependence of inositol 1,4,5-trisphosphate-induced Ca2+ release in smooth muscle cells of the guinea pig taenia caeci. J Gen Physiol 95 1103-1122 Iizuka K, Yoshii A, Dobashi K, Horie T, More M, Nakazawa T 1998 InsP3, but not novel Ca2+ releasers, contributes to agonist-initiated contraction in rabbit airway smooth muscle. J Physiol 511 915-933... 

Bulbring E, T omita T 1969 Effect of calcium, barium and manganese on the action of adrenaline in the smooth muscle of the guinea-pig taenia coli. Proc R Soc Lond B Biol Sci 172 121-136 Marchant JS, Taylor CW 1998 Rapid activation and partial inactivation of inositol trisphosphate receptors by inositol trisphosphate. Biochemistry 37 11524-11533 Somlyo AV, Horiuti K, Trentham DR, Kitazawa T, Somlyo AP 1992 Kinetics of Ca2+ release and contraction induced by photolysis of caged D-myo-inositol 1,4,5-trisphosphate in smooth muscle the effects of heparin, procaine, and adenine nucleotides. J Biol Chem 267 22316-22322... 

Somlyo AP, Somlyo AV 2000 Signal transduction by G-proteins, Rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol 522 177—185 Somlyo AP, Devine CE, Somlyo AV, N orth SR 1971 Sarcoplasmicreticulumand the temperature-dependent contraction of smooth muscle in calcium-free solutions. J Cell Biol 51 722—741 Somlyo AP, Walker JW, Goldman YE et al 1988 Inositol trisphosphate, calcium and muscle contraction. Philos Trans R Soc Lond B Biol Sci 320 399 114 Somlyo AP, Wu X, Walker LA, Somlyo AV 1999 Pharmacomechanical coupling the role of calcium, G-proteins, kinases and phosphatases. Rev Physiol Biochem Pharmacol 134 201-234... 

Figure 22.4 Injury to endothelial cells can lead to vasospasm. Normal endothelial cells release nitric oxide (NO) which relaxes smooth muscle this is achieved by nitric oxide increasing the concentration of cyclic GMP within smooth muscle fibres and cyclic GMP relaxing the smooth muscle. Injured endothelial cells secrete very little nitric oxide but secrete more endothelin. The latter increases the formation of inositol trisphosphate (IP3), which binds to the sarcoplasmic reticulum (SR) where it stimulates the Ca ion channel. The Ca ion channel in the plasma membrane is also activated. Both effects result in an increase in cytosolic Ca ion concentration, which then stimulates contraction (vasospasm). This reduces the diameter of the lumen of the artery.

Figure 22.13 a-Adrenergic receptor control of contraction of smooth muscle. IP3 represents inositol trisphosphate. Binding of a catecholamine to an a-receptor activates a membrane-bound phospholipase which hydrolyses phosphatidyUnositol bisphosphate within the membrane to produce IP, and diacylglycerol (DAG). IP3 binds a receptor on the sarcoplasmic reticulum in smooth muscle, which activates a Ca ion channel and the cytosolic Ca ion concentration increases, which results in contraction of smooth muscle in arterioles. This results in vasoconstriction and hence decreases blood flow which can leading to an increase in blood pressure. 

The same basic biochemical control mechanism causes contraction of the smooth muscle as well as secretion of aldosterone. The binding of angiotensin to its receptor activates a membrane phospholipase-C. It catalyses the hydrolysis of phosphoinositide phosphatidylinositol bis-phosphate to produce the two intracellular messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). 

Activation of phospholipase C leads to cleavage of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). 1P3 promotes release of Ca2+ from storage organelles, whereby contraction of smooth muscle cells, breakdown of glycogen, or exocytosis may be initiated. DAG stimulates protein kinase C, which phosphorylates certain serine- or threonine-containing enzymes. 

The opposing effects on smooth muscle (A) of a- and p-adrenoceptor activation are due to differences in signal transduction, ai -Receptor stimulation leads to intracellular release of Ca2+ via activation of the inositol trisphosphate (IP3) pathway. In concert with the protein calmodulin, Ca2+ can activate myosin kinase, leading to a rise in tonus via phosphorylation of the contractile protein myosin (— vasoconstriction). 012-Adrenoceptors can also elicit a contraction of smooth muscle cells by activating phospholipase C (PLC) via the py-subunits of G, proteins. 

Chilvers, E.R., Giembycz, M.A., Challis, R.A.J., Barnes, P.J. and Nahorski, S.R. (1991). Lack of effect of zaprinast on methacholine-induced contraction and inositol 1,4,5 trisphosphate accumulation in bovine tracheal smooth muscle. Br. J. Pharmacol. 103, 1119-1125. 

Hashimoto, T., Hirata, M. and Ito, Y. (1985). A role for inositol 1,4,5-trisphosphate in the initiation of sgonist-induced contractions of dog tracheal smooth muscle. Br. J. Pharmacol. 86, 191-199. 

Somlyo, A.V., Bond, M., Somlyo, A.P., and Scarpa, A. (1985) Inositol trisphosphate-induced calcium release and contraction in vascular smooth muscle. Proc.Natl.Acad.Sci.USA, 82 5231-5235. 

Somlyo AV (1980) Ultrastructure of vascular smooth muscle. The Handbook of Physiology The Cardiovascular System, Vol. II Vascular Smooth Muscle. DF Bohr, AP Somlyo, HV Sparks, eds., American Physiological Society, Bethesda, Md., pp. 33-67. Somlyo AV, Bond, M, Somlyo, AP Scarpa, A (1985) Inositol trisphosphate- induced calcium release and contraction in vascular smooth muscle. Proc Natl Acad Sci USA 82 5231-5235... 

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