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Structure Smooth muscle is spindle shaped, and like any muscle, can contract and relax. In relaxed state, each cell is spindle-shaped, 25-50 µm long and 5 µm wide.The cells that compose smooth muscle have single nuclei. The cells themselves are generally arranged in sheets or bundles and connected by gap junctions. In order to contract the cells contains intracellular contractile filamentous proteins called actin and myosin. While the filaments are essentially the same in smooth muscle as they are in skeletal and cardiac muscle, the way they are arranged is different. As non-striated muscle, the actin and myosin is not arranged into distinct sarcomeres that form orderly bands throughout the muscle cell. However there is an organized cytoskeleton and actin thin filaments attach to the sarcolemma by focal adhesions or attachment plaques. The sarcolemma of smooth muscle cells possess microdomains specialized to cell signalling events and ion channels called caveolae. These invaginations in the sarcoplasma contain a host of receptors (prostacyclin, endothelin, serotonin, muscarinic receptors, adrenergic receptors), second messenger generators (adenylate cyclase, Phospholipase C), G proteins (RhoA, G alpha), kinases (rho kinase-ROCK, Protein kinase C, Protein Kinase A) , ion channels (L type Calcium channels, ATP sensitive Potassium channels, Calcium sensitive Potassium channels)in close proximity. The caveolae are often in close proximity to sarcoplasmic reticulum or mitochondria indicative of their metabolic activity. Some smooth muscle preparations can be visualized contracting in a spiral corkscrew fashion, and contractile proteins can organize into zones of high concentrations of actin and myosin and appear as contractile nodes along the axis of the smooth muscle cell. Function The contractile function of this muscle, to a large extent, determines function of the organ. For example, contractile function of vascular smooth muscle is critical to regulating the lumenal diameter of the small arteries-arterioles called resistance vessels, but in the larger elastic arteris it contributes to the viscoelastic properties of the vascular wall and minimally alters the lumenal diameter. The resistant arteries contribute significantly to setting the level of blood pressure. Smooth muscle tissue serves to transport food, urine, sperm and ova, and bile by means of controlled peristaltic contractions that massage products through organ lumens. Smooth muscle in the skin is responsible for goose bumps. Smooth muscle of the iris controls light reaching the retinae. Contraction and Relaxation Smooth muscle contraction is caused by the sliding of myosin and actin fibres over each other. The energy for this to happen is provided by hydrolysis of ATP. Movement of the fibres over each other happens when heads on the myosin fibres form crossbridges with the actin fibre. These heads tilt and drag the actin fibre a small distance. The heads then release the actin fibre and adopt their original conformation. They can then re-bind to another part of the actin molecule and drag it along further. This process is called crossbridge cycling and is the same for all muscles. Crossbridge cycling, though, cannot occur until the myosin heads have been activated to allow crossbridges to form. The myosin heads are made up of heavy chains and 20 kilodalton "light" protein chains. When the light chains are phosphorylated it becomes active and will allow contraction to occur. The enzyme that phosphorylates the light chains is called myosin light chain kinase (MLCK). In order to control contraction, MLCK will only work when the muscle is stimulated to contract. Stimulation will increase the intracellular concentration of calcium ions. These bind to a molecule called calmodulin and form a calcium-calmodulin complex. It is this complex that will bind to MLCK to activate it, allowing the chain of reactions for contraction to occur. Smooth muscle does not contain troponin, but contains tropomyosin and other thin filament proteins such as calponin and caldesmon. The phosphorylation of the thin filament proteins caldesmon and calponin by various kinases is also believed to function in smooth muscle contraction.These thin filament proteins generally are inhibitory to the calcium activated myosin ATPase. There is evidence that phosphorylation of caldesmon and calponin by various kinases dissociates them from actin or alters their inhibitory activity. Smooth muscle can be characterized as two types:tonic and phasic which describes their response to depolarizing high potassium solutions. The tonic contracts and relaxes slowly and exhibits force maintenance. The phasic smooth muscle contracts and relaxes rapidly. Differences in myosin isoforms contributes to the difference in shortening velocities between tissues. Contractions in vertebrate smooth muscle can be initiated by stretch, gap junction electrical, and neural and humoral agents. Phasic smooth muscle in the gastrointestinal and urogenital tracts is regulated by the enteric nervous system and by peristaltic pacemaker cells- the interstitial cells of Cajal. Stretch, neural and humoral agents, and gap junction activity that depolarize the sarcolemma increase intracellular calcium by extracellular calcium entering through L type calcium channels and intracellular calcium release predominately from the sarcoplasmic reticulum. Calcium release from the sarcoplasmic reticulum is from Ryanodine receptor channels (Calcium sparks) by a redox process and Inositol triphosphate receptor channels by the second messenger inositol triphosphate. The intracellular calcium binds with calmodulin which then binds and activates myosin-light chain kinase. The calcium-calmodulin-myosin light chain kinase complex phosphorylates the 20 kilodalton (kd) myosin light chains on amino acid residue-serine 19 to initiate contraction. The phosphorylation of the myosin light chains then allows the myosin ATPase to function. Phosphorylation of the 20 kd myosin light chains correlates well with the shortening velocity of smooth muscle. During this period there is a rapid burst of energy utilization as measured by oxygen consumption. Within a few minutes of initiation the calcium level markedly decrease, 20 kd myosin light chains phosphorylation decreases, and energy utilization decreases, however there is a sustained maintenance of force in tonic smooth muscle. The sustained phase has been attributed to slowly cycling dephosphorylated myosin crossbridges and has been termed latch-bridges. During contraction of muscle, rapidly cycling crossbridges form between activated actin and phosphorylated myosin generating force. During the sustained phase, phosphorylation levels decline and slow cycling dephosphorylated crossbridges act as latch bridges to maintain the force at low energy costs. A number of kinases (Protein kinase C, ROCK kinase, Zip kinase) have been implicated as important cell signalling molecules during the sustained phase, and calcium flux may play a role. Phosphorylation of the 20kd myosin light chains is counteracted by a myosin light chain phosphatase that dephosphorylates the myosin light chains. In vitro smooth muscle contractions with depolarizing high potassium balanced saline generates a certain amount of force. The same preparation stimulated in normal balanced saline with an agonist such as endothelin or serotonin will generate more force. This increase in force is termed calcium sensitization. The myosin light chain phosphatase is inhibited to increase the gain or sensitivity of myosin light chain kinase to calcium. There are number of cell signalling pathways believed to regulate this decrease in myosin light chain phosphatase: a RhoA-Rock kinase pathway, a Protein kinase C-Protein kinase C potentiation inhibitor protein 17 (CPI-17)pathway, telokin, and a Zip kinase pathway. Further Rock kinase and Zip kinase have been implicated to directly phosphorylate the 20kd myosin light chains. The relaxation of smooth muscle is mediated by the Endothelium-derived relaxing factor-nitric oxide, endothelial derived hyperpolarizing factor (either an endogenous cannabinoid, cytochrome P450 metabolite, or hydrogen peroxide), or prostacyclin (PGI2). Nitric oxide and PGI2 stimulate soluble guanylate cyclase and membrane bound adenylate cyclase, respectively. These cyclic nucleotides activate Protein Kinase G and Proten Kinase A and phosphorylate a number of proteins. The phosphorylation events lead to a decrease in intracelluar calcium (inhibit L type Calcium channels, inhibits IP3 receptor channels, stimulates sarcoplasmic reticulum Calcium pump ATPase), a decrease in the 20kd myosin light chain phosphorylation by altering calcium sensitization and increasing myosin light chain phosphatase activity,a stimulation of calcium sensitive potassium channels which hyperpolarize the cell, and the phosphorylation of a small heat shock protein (hsp20) that alters actin thin filament interaction with myosin all contributing to relaxation. The endothelium derived hyperpolarizing factor stimulates calcium sensitive potassium channels and/or ATP sensitive potassium channels and stimulate potassium efflux which hyperpolarizes the cell and produces relaxation. In invertebrate smooth muscle, contraction is initiated with calcium directly binding to myosin and then rapidly cycling cross-bridges generating force. Similar to vertebrate smooth muscle there is a low calcium and low energy utilization catch phase. This sustained phase or catch phase has been attribute to a catch protein that is similar to myosin light chain kinase and titin called twitchin. Control Smooth muscle cells can be stimulated to contract or relax in many different ways. They may be directly stimulated by the autonomic nervous system ("involuntarily" control), but can also react on stimuli from neighbouring cells and on hormones (vasodilators or vasoconstrictor) within the medium that it carries. Growth and rearrangement The mechanism in which external factors stimulate growth and rearrangement is not yet fully understood. A number of growth factors and neurohumoral agents influence smooth muscle growth and differentiation. There is a signficant correlation between protein kinase G expression and a contractile smooth muscle phenotype. The cells are able to produce their own extracellular matrix. When cultured outside the body, the cells tend to differentiate into a synthetic phenotype, which is not able to contract. The embryological origin of smooth muscle varies, but is usually of mesodermal origin. However, the Great Arteries of the heart are derived from ectomesenchyme of neural crest origin, although coronary artery smooth muscle is of mesodermal origin. Related diseases "Smooth muscle condition" is a condition in which the body of a developing embryo does not create enough smooth muscle for the gastrointestinal system. This condition is fatal. Anti-smooth muscle antibodies (ASMA) can be a symptom of an auto-immune disorder, such as hepatitis, cirrhosis, or lupus. See also | ||||||||||
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