Smooth muscle activation protein kinase

MLCK itself is phosphorylated by cyclic-AMP activated protein kinase, (protein kinase A) and cyclic-GMP activated protein kinase, (protein kinase G). Protein kinase A will phosphorylate MLCK at two sites and protein kinase G at one in some cases and two in others. These differences seem to be important in how the individual smooth muscle cells are regulated. 

If MLCK activates contraction by increasing myosin phosphorylation, then an increase in the activity of myosin light chain phosphatase, MLCP, by decreasing the fraction of myosin which is phosphorylated, should lead to relaxation from the active (contractile) state. Cyclic adenosine monophosphate (AMP) is a strong inhibitor of smooth muscle contraction and it has been suggested that activation of MLCP could result from its phosphorylation via cAMP activated protein kinase (see Figure 5). 

Mori-Abe A, Tsutsumi S, Takahashi K, Toya M, Yoshida M, Du B, Kawagoe J, Naka-hara K, Takahashi T, Ohmichi M, Kurachi H (2003) Estrogen and raloxifene induce apoptosis by activating p38 mitogen-activated protein kinase cascade in synthetic vascular smooth muscle cells. J Endocrinol 178 417-426... 

Several of the proteins that mediate Ca2+ flow in and out of SR have been identified. Oxalate-facilitated Ca2+ uptake into the SR and in vitro biochemical studies of purified SR identified it as an ATP-driven Ca2+ pump (SERCA pump reviewed in Himpens et al 1995) that is inhibited by thapsigargin and cyclopiazonic acid and regulated, at least in some smooth muscles, by phosphorylation of phospholamban by cyclic nucleotide-activated protein kinase(s) (Karczewski et al 1998). 

Rakhit, S., Conway, A-M., Tate, R., Bower, T, Pyne, N.J. and Pyne, S., 1999, Sphingosine 1-phosphate stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle role of endothelial differentiation gene-1, c-Src tyrosine kinase and phosphoinositide 3-kinase. Biochem. J. 338 643-649. 

Answer C. Nitroprusside is metabolized to produce nitric oxide, NO, normally produced by the vascular endothelium, stimulates the cyclase in vascular smooth muscle to increase cGMP, activate protein kinase G, and cause relaxation. 

All muscarinic receptors are members of the seven transmembrane domain, G protein-coupled receptors, and they are structurally and functionally unrelated to nicotinic ACh receptors. Activation of muscarinic receptors by an agonist triggers the release of an intracellular G-protein complex that can specifically activate one or more signal transduction pathways. Fortunately, the cellular responses elicited by odd- versus even-numbered receptor subtypes can be conveniently distinguished. Activation of Ml, M3, and M5 receptors produces an inosine triphosphate (IP3) mediated release of intracellular calcium, the release of diacylglyc-erol (which can activate protein kinase C), and stimulation of adenylyl cyclase. These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle. 

Diep, Q. N., Touyz, R. M., and Schiffrin, E. L. (2000). Docosahexaenoic acid, a peroxisome proliferator-activated receptors-a ligand induces apoptosis in vascular smooth muscle cells by stimulation of p38 mitogen-activated protein kinase. Hypertension 36, 851-855. 

The diacylglycerols released by phospholipase C diffuse laterally through the bilayer and, together with the incoming Ca2+, activate protein kinases C. These kinases also require phosphatidylserine for their activity and phosphorylate serine and threonine side chains in a variety of proteins.329 330b They are stimulated by the released unsaturated diacylglycerols. In addition protein kinases C can be activated by phorbol esters, which are the best known tumor promoters (Box 11-D). The diacylglycerol requirement favors a function for these protein kinases in membranes. They also appear to cooperate with calmodulin to activate the Ca2+-dependent contraction of smooth muscle.330... 

FIGURE 26-1 Mechanism of action of beta agonists on respiratory smooth muscle. Beta agonists facilitate bronchodilation by stimulating adenyl cyclase activity, which in turn increases intracellular cyclic AMP production. Cyclic AMP activates protein kinase, which appears to add an inhibitory phosphate group to contractile proteins, thus causing muscle relaxation and bronchodilation. 

Geraldes R Sirois MG, Bernatchez PN, Tanguay JE Estrogen regulation of endothelial and smooth muscle cell migration and proliferation role of p38 and p42/44 mitogen-activated protein kinase. Arterioscler Thromb Vase Biol 2002 22 1585-1590. 

Graves LM, Bomfeldt KE, Raines EW, Potts BC, Macdonald SG, Ross R, Krebs EG. 1993. Protein kinase A antagonizes platelet-derived growth factor-induced signaling by mitogen activated protein kinase in human arterial smooth muscle cells. Proc Natl Acad Sci USA 90 10300-10304. 

Eguchi, S., Matsumoto, T., Motley, E. D., et al. 1996. Identification of an essential signaling cascade for mitogen-activated protein kinase activation by angiotensin II in cultured rat vascular smooth muscle cells. Possible requirement of Gq-mediated p21ras activation coupled to a Ca2+/calmodulin-sensitive tyrosine kinase. J Biol Chem 271 14169-14175. 

Eguchi, S., Numaguchi, K., Iwasaki, H., et al. 1998. Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. J Biol Chem 273 8890-8896. 

Ushio-Fukai, M., Alexander, R. W., Akers, M., et al. 1998a. p38 mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin II. Role in vascular smooth muscle cell hypertrophy. J Biol Chem 273 15022-15029. 

Eguchi, S., Numaguchi, K., Iwasaki, H., Matsumoto, T., Yamakawa, T., Utsunomiya, H., Motley, E.D., Kawakatsu, H., Owada, K.M., Hirata, Y., Marumo, F., and Inagami, T. 1998. Calcium-dependent epidermal growth factor receptor transactivaiton mediates the angiotensin Il-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. J. Biol. Chem. 273 8890-8896. 

Tabet, F., E.L. Schiffrin, and R.M. Touyz. 2005. Mitogen-activated protein kinase activation by hydrogen peroxide is mediated through tyrosine kinase-dependent, protein kinase C-independent pathways in vascular smooth muscle cells upregulation in spontaneously hypertensive rats. J. Hypertens. 23 2005-2012. 

H. Satoh, M. Togo, M. Hara, T. Miyata, K. Han, H. Maekawa, N. Ohno, Y. Hashimoto, K. Kurokawa, and T. Watanabe, Advanced glycation endproducts stimulate mitogen-activated protein kinase and proliferation in rabbit vascular smooth muscle cells, Biochem. Biophys. Res. Comm., 1997, 239, 111-115. 

Inhibits NAD(P)H oxidase cytochrome b558 activity, increases oxidant production by the mitochondria and inhibits ASMC proliferation and phosphorylation of the ERK1/2 mitogen-activated protein kinase and expression of cyclin D1 in human airway smooth muscle [74]... 

Figure 6.10. Calcium-dependent signalling by adrenergic receptors. a p-Adrenergic receptors activate adenylate cyclase. cAMP activates protein kinase A (PKA). In heart muscle, PKA phospho-rylates several Ca transporters and charmels, so that the amount of Ca available for contraction is increased. PL Phospholam-ban SERCA SR/ER Ca transporter, b In smooth muscle, myosin activation in works by way of phosphorylation, which is performed by myosin light chain kinase (MLCK). Inactivation is accomplished by myosin light chain phosphatase (MLCP). c aj-Adrenergic receptors stimulate phospholipase C, which releases inositoltriphosphate (IP3). IP3 binds to a cognate ligand-gated Ca chaimel in the ER and releases Ca, which with calmodulin activates MLCK.

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