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Minocycline

By H. Sigmor. Lyme Academy of Fine Arts.

Mitochondria are lo- important because the narrowing of a blood vessel has a cated at the ends of the nucleus and near the surface mem- powerful influence on the rate of blood flow through it (see brane purchase minocycline 50 mg fast delivery bacteria 90. In some smooth muscle cells order minocycline 50 mg visa bacterial skin infection, the SR is abundant, al- Chapters 12 and 15). This circular arrangement is also though not to the extent found in skeletal muscle. In some prominent in the airways of the lungs, where it regulates cases, it closely approaches the cell membrane, but there is the flow of air. A further specialization of the circular muscle arrange- The bulk of the cell interior is occupied by three types ment is a sphincter, a thickening of the muscular portion of of myofilaments: thick, thin, and intermediate. The thin fil- the wall of a hollow or tubular organ, whose contraction aments are similar to those of skeletal muscle but lack the CHAPTER 9 Skeletal Muscle and Smooth Muscle 167 Dense body Mitochondrion Myofilaments Caveoli Autonomic nerve fiber Gap junction Nucleus Connective tissue fibers FIGURE 9. General smooth muscle, showing cells in cross sec- Histology of the Mammal. The length of the individual fil- filaments and to transmit the force of contraction to adja- aments is not known with certainty because of their irregu- cent cells. The thick filaments are composed of Smooth muscle lacks the regular sarcomere structure of myosin molecules, as in skeletal muscle, but the details of skeletal muscle. Studies have shown some association the exact arrangement of the individual molecules into fila- among dense bodies down the length of a cell and a ten- ments are not completely understood. The thick filaments dency of thick filaments to show a degree of lateral group- appear to be approximately 2. However, it appears that the lack of a strongly periodic than in skeletal muscle (1. The intermediate fila- arrangement of the contractile apparatus is an adaptation of ments are so named because their diameter of 10 nm is be- smooth muscle associated with its ability to function over a tween that of the thick and thin filaments. Intermediate fil- wide range of lengths and to develop high forces despite a aments appear to have a cytoskeletal, rather than a smaller cellular myosin content. Prominent throughout the cytoplasm are small, dark-staining areas called dense bodies. Because smooth muscle cells are associated with the thin and intermediate filaments and are so small compared to the whole tissue, some mechanical considered analogous to the Z lines of skeletal muscle. In- Dense bodies associated with the cell margins are often dividual cells are coupled mechanically in several ways. A called membrane-associated dense bodies (or patches) or proposed arrangement of the smooth muscle contractile focal adhesions. They appear to serve as anchors for thin and force transmission system is shown in Figure 9. This 168 PART III MUSCLE PHYSIOLOGY Cell-to-cell phenomenon is under hormonal control; in the uterus, for Paired membrane-associated Myofilaments inserting connective example, gap junctions are rare during most of pregnancy, dense bodies in membrane-associated tissue strands and the contractions of the muscle are weak and lack coor- dense body dination. However, just prior to the onset of labor, the number and size of gap junctions increase dramatically and the contractions become strong and well coordinated. Nucleus Shortly after the cessation of labor, these gap junctions dis- appear and tissue function again becomes less coordinated. Electrical coupling among smooth muscle cells is the ba- sis for classifying smooth muscle into two major types: • Multiunit smooth muscle, which has little cell-to-cell Collagen and elastin communication and depends directly on nerve stimula- fibers between cells tion for activation (like skeletal muscle). Its cells form a The contractile system and cell-to-cell con- functional syncytium (an arrangement in which many FIGURE 9. Note regions of association between thick and thin filaments that are anchored by up the bulk of the muscle in the visceral organs. A net- work of intermediate filaments provides some spatial organization (see, especially, the left side). Several types of cell-to-cell me- The Regulation and Control of chanical connections are shown, including direct connections and connections to the extracellular connective tissue matrix. Struc- Smooth Muscle Involve Many Factors tures are not necessarily drawn to scale. In addition to contraction picture represents a consensus from many researchers and in response to nerve stimulation, smooth muscle responds areas of investigation. Note that assemblies of myofila- to hormonal and pharmacological stimuli, the presence or ments are anchored within the cell by the dense bodies and lack of metabolites, cold, pressure, and stretch, or touch, at the cell margins by the membrane-associated dense bod- and it may be spontaneously active as well. The contractile apparatus lies oblique to the long axis ity of controlling factors is vital for the integration of of the cell. When single isolated smooth muscle cells con- smooth muscle into overall body function.

These properties are shared by several endogenous steroids (synthesised in the brain or adrenal glands) buy minocycline 50 mg free shipping antimicrobial door handles,the most potent being the reduced metabolite of progesterone minocycline 50 mg with amex antibiotic mnemonics,3a-hydroxy-5a-pregnan-20-one (allopregnanolone or 3a,5a- THP) and the reduced metabolite of dexoycorticosterone,3a,21-dihydroxy-5a-pregnan- 20-one (allotetrahydrodeoxycorticosterone or a-THDOC). Particular interest in these compounds stems from the fact that they may act as endogenous modulators of GABAA receptors and their levels are altered by stress as well as during the menstrual cycle and pregnancy. For example,during menstruation decreasing levels of progesterone result in a decline in the production of allopregnanolone. Recently it has been demonstrated that such an abrupt decline (akin to drug withdrawal) can cause changes in the properties of GABAA receptors that may underlie the symptoms associated with premenstrual syndrome,including increased susceptibility to seizures and insensitivity to benzodiazepine agonists. Steroids appear to act at a distinct site on the GABA- receptor complex,as flumazenil does not block their action,and the ClÀ currents they evoke directly can be potentiated by barbiturates (and vice versa). The 3b-methyl- substituted synthetic analogue of allopregnanolone,ganaxolone (3a-hydroxy-3b- methyl-5a-pregnan-20-one) is less easily metabolised than its endogenous parent 238 NEUROTRANSMITTERS,DRUGS AND BRAIN FUNCTION compound,allowing activity following oral administration,and is currently under investigation as an anticonvulsant. Anaesthetics Steroids,such as alphaxolone,and barbiturates,such as thiopentone,represent only two classes of the many structurally diverse molecules found to induce general anaesthesia. Although a number of these clearly have actions on a range of targets,including glycine,5- HT3,nicotinic and glutamate receptors,all,with the exception of the dissociative anaesthetic ketamine,have an effect on GABAA receptors at relevant concentrations. For example,the intravenous anaesthetic agents propofol,propanidid and etomidate markedly enhance responses to GABA (apparently by prolonging bursts of ClÀ channel openings) and are capable of directly evoking ClÀ currents. The currents produced by these agents at high doses,as well as those caused by steroids and barbiturates,are blocked by bicuculline,indicating that they are due to activation of the ClÀ channel associated with the GABAA receptor. It is also now clear that volatile anaesthetics such as halothane and isoflurane as well as alcohols (including ethanol),rather than having non-specific membrane-disrupting actions,owe at least some of their properties to a potentiation of GABA responses,through a direct interaction with sites on GABAA receptors. STRUCTURE OF GABAA RECEPTORS Over the past decade or so significant advances have been made in our understanding of the structure of the GABAA receptor,which is now known to be formed by the assembly of multiple subunit proteins. In 1987 two subunits of the receptor,designated a and b, were cloned (Schofield et al. Following on from this work,16 mammalian subunits encoded by distinct genes have now been identified. These genes encode proteins of approximately 450±550 amino acids (depending on the species) which,according to their sequence similarities,have been grouped into seven families Ð a, b, g, d, e, p and y (Barnard et al. The a, b and g families contain multiple isoforms (a1±a6, b1±b3 and g1±g3) and in a number of cases additional complexity is generated by alternative mRNA splicing. The subunits share varying degrees of sequence identity but have a similar predicted tertiary structure. This consists of four membrane-spanning a-helices (M1±M4),a large extracellular N-terminal region,a large intracellular domain between M3 and M4 and a short extracellular C-terminal portion (Fig. The highest degree of conservation is in the transmembrane regions and the greatest variation in the intracellular loop between M3 and M4. The extracellular domain contains potential N-linked glycosylation sites and a b-loop formed by a disulphide bridge between two cysteine residues. The intracellular loops of b and g subunits contain sites for phosphorylation by a variety of protein kinases,including cAMP-dependent protein kinase,cGMP- dependent protein kinase,protein kinase C,Ca2‡/calmodulin-dependent protein kinase and tyrosine kinase,which may be important in the regulation of receptor function. These general features are very similar to those of two other ligand-gated ion channels, the nicotinic acetylcholine receptor and the glycine receptor (see below) and there is a considerable degree of sequence homology among these proteins. By analogy with the nicotinic acetylcholine receptor,it is thought that the GABAA receptor is formed by the assembly of five subunits around a central ion channel,with the M2 region of each subunit forming the lining of the channel (Fig. The suggested stoichiometry of the most widely expressed form of receptor is 2a,2b and 1g. Shown below are the possible subunit combinations of one such benzodiazepine-sensitive receptor together with a benzodiazepine-insensitive receptor in which the g subunit is replaced by a d,and a p-containing receptor with four different subunit types Subunit combinations and receptor function Expression studies in Xenopus oocytes or transfected cell lines originally suggested that functional GABA-activated chloride channels could be formed by receptor subunits of each class in isolation. However,much better expression occurs with two or more subunit types in combination and it is likely that most native receptors contain at least three different subunits. Co-expression of a and b subunits results in the assembly of 240 NEUROTRANSMITTERS,DRUGS AND BRAIN FUNCTION functional receptors that can be activated by GABA and are sensitive to the antagonists bicuculline and picrotoxin and show modulation by barbiturates. But only when a g subunit is expressed in conjunction with an a and a b subunit is benzodiazepine binding and potentiation of GABA seen. As benzodiazepines do not bind to g subunits alone,it is likely that the conformation of the receptor is appropriate for benzodiazepine binding only when all three subunit types are present.

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