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Public Interest Law Initiative

Synthroid

By T. Zakosh. Coker College.

In addition to the proteins di- often called the “tail” region cheap synthroid 50mcg fast delivery medicine 750 dollars, composed of light meromyosin rectly involved in the process of contraction quality synthroid 125mcg symptoms 5 days after iui, there are sev- (LMM). The remainder of the molecule, heavy meromyosin eral other important structural proteins. Titin, a large fila- (HMM), consists of a protein chain that terminates in a mentous protein, extends from the Z lines to the bare Tropomyosin Troponin Tn-T Tn-I Tn-C G-actin monomers Regulatory protein complex F-actin filament FIGURE 8. Nebulin, a filamentous protein Head portion that extends along the thin filaments, may play a role in sta- Tail portion S2 bilizing thin filament length during muscle development. The protein -actinin, associated with the Z lines, serves to S1 S1 Head Actin- anchor the thin filaments to the structure of the Z line. External to the cells, the protein laminin site forms a link between integrins and the extracellular matrix. S2 These proteins are disrupted in the group of genetic dis- eases collectively called muscular dystrophy, and their lack or malfunction leads to muscle degeneration and weakness and death (see Clinical Focus Box 8. Polymyositis is an inflammatory disorder that produces Myosin filament damage to several or many muscles (Clinical Focus Box 8. The progressive muscle weakness in polymyositis usu- ally develops more rapidly than in muscular dystrophy. New York: Springer-Verlag, tween the surface membrane and contractile filaments. In several forms of mus- these diseases is Duchenne’s muscular dystrophy cular dystrophy, both laminin and dystrophin are lacking (DMD) (also called pseudohypertrophic MD), which is an or defective. X-linked hereditary disease affecting mostly male children A disease as common and devastating as DMD has long (1 of 3,500 live male births). The recent identifica- gressive muscular weakness during the growing years, be- tion of three animals—dog, cat, and mouse—in which ge- coming apparent by age 4. A characteristic enlargement of netically similar conditions occur promises to offer signifi- the affected muscles, especially the calf muscles, is due to cant new opportunities for study. The manifestation of the a gradual degeneration and necrosis of muscle fibers and defect is different in each of the three animals (and also dif- their replacement by fibrous and fatty tissue. The mdx most sufferers are no longer ambulatory, and death usu- mouse, although it lacks dystrophin, does not suffer the ally occurs by the late teens or early twenties. Re- rious defects are in skeletal muscle, but smooth and car- search is underway to identify dystrophin-related proteins diac muscle are affected as well, and many patients suffer that may help compensate for the major defect. A related (and cause of their rapid growth, are ideal for studying the nor- rarer) disease, Becker’s muscular dystrophy (BMD), mal expression and function of dystrophin. Progress has has similar symptoms but is less severe; BMD patients of- been made in transplanting normal muscle cells into mdx ten survive into adulthood. Some six other rarer forms of mice, where they have expressed the dystrophin protein. A Using the genetic technique of chromosome mapping gene expressing a truncated form of dystrophin, called (using linkage analysis and positional cloning), re- utrophin, has been inserted into mice using transgenic searchers have localized the gene responsible for both methods and has corrected the myopathy. DMD and BMD to the p21 region of the X chromosome, The mdx dog, which suffers a more severe and human- and the gene itself has been cloned. It is a large gene of like form of the disease, offers an opportunity to test new some 2. About shows prominent muscle fiber hypertrophy, a poorly un- one third of DMD cases are due to new mutations and the derstood phenomenon in the human disease. Taking ad- other two thirds to sex-linked transmission of the defective vantage of the differences among these models promises gene. The BMD gene is a less severely damaged allele of to shed light on many missing aspects of our understand- the DMD gene. The product of the DMD gene is dystrophin, a large pro- tein that is absent in the muscles of DMD patients. The function of dy- References strophin in normal muscle appears to be that of a Burkin DJ, Kaufman SJ. The alpha7beta1 integrin in mus- cytoskeletal component associated with the inside surface cle development and disease.

Only a few second messengers are responsible for relaying these sig- Gene Enzyme P P nals within target cells buy discount synthroid 125 mcg line symptoms 6 days before period, and because each target cell has a Ion channel different complement of intracellular signaling pathways 50mcg synthroid amex medications interactions, the physiological responses can vary. Activation the same messenger can elicit a distinct physiological re- of adenylyl cyclase results in increased cytosolic levels of cAMP. For example, the neurotrans- Two molecules of cAMP bind to each of the regulatory subunits, mitter acetylcholine can cause heart muscle to relax, skele- leading to the release of the active catalytic subunits. This phosphorylation alters the activ- As a result of binding to specific G-protein-coupled recep- ity or function of the target proteins and ultimately leads to tors, many peptide hormones and catecholamines produce a desired cellular response. However, in addition to acti- an almost immediate increase in the intracellular concen- vating protein kinase A and phosphorylating target pro- tration of cAMP. For these ligands, the receptor is coupled teins, in some cell types, cAMP directly binds to and affects to a stimulatory G protein (G ), which upon activation the activity of ion channels. When cAMP concentrations in the cell are low, the second messenger, cAMP. When duction of cAMP through a receptor coupled to G s, some cAMP is formed in response to hormonal stimulation, two hormones act to decrease cAMP formation and, therefore, molecules of cAMP bind to each of the regulatory subunits, have opposing intracellular effects. These hormones bind causing them to dissociate from the catalytic subunits. This to receptors that are coupled to an inhibitory (G i) rather relieves the inhibition of catalytic subunits and allows them than a stimulatory (G s) G protein. The intracellular signal provided by cGMP Is an Important Second Messenger in cAMP is rapidly terminated by its hydrolysis to 5 AMP by Smooth Muscle and Sensory Cells a group of enzymes known as phosphodiesterases, which cGMP, a second messenger similar and parallel to cAMP, is are also regulated by hormones in some instances. Although the full role of cGMP as a second messenger is not as well understood, its importance is finally being ap- Protein Kinase A Is the Major Mediator preciated with respect to signal transduction in sensory tis- of the Signaling Effects of cAMP sues (see Chapter 4) and smooth muscle tissues (see Chap- cAMP activates an enzyme, protein kinase A (or cAMP-de- ters 9 and 16). The production of cGMP is mainly regulated by the activation of a cytoplasmic form of guanylyl cyclase, a target of the paracrine mediator nitric oxide (NO) that is produced by endothelial as well as other cell types and can mediate smooth muscle relaxation (see Chapter 16). Atrial natriuretic peptide and guanylin (an in- testinal hormone) also use cGMP as a second messenger, and in these cases, the plasma membrane receptors for these PIP PIP2 hormones express guanylyl cyclase activity. PLC DAG Second Messengers 1,2-Diacylglycerol (DAG) PI and Inositol Trisphosphate (IP3) Are Generated by the Hydrolysis of Phosphatidylinositol 4,5-Bisphosphate (PIP ) P 2 IP3 1 P 1 Some G-protein-coupled receptors are coupled to a differ- 5 ent effector enzyme, phospholipase C (PLC), which is lo- 5 P P calized to the inner leaflet of the plasma membrane. Similar 4 P P to other GPCRs, binding of ligand or agonist to the recep- tor results in activation of the associated G protein, usually Inositol IP IP2 G q (or Gq). Depending on the isoform of the G protein as- CDP-diacylglycerol Phosphatidic sociated with the receptor, either the or the subunit acid may stimulate PLC. Stimulation of PLC results in the hy- drolysis of the membrane phospholipid, phosphatidylinosi- B tol 4,5-bisphosphate (PIP2), into 1,2-diacylglycerol (DAG) and inositol trisphosphate (IP3). In its second messenger role, DAG accumulates in the plasma membrane and activates the membrane-bound cal- R cium- and lipid-sensitive enzyme protein kinase C (see Fig. When activated, this enzyme catalyzes the phos- Protein phorylation of specific proteins, including other enzymes PIP2 PLC DAG kinase C and transcription factors, in the cell to produce appropriate physiological effects, such as cell proliferation. Several tu- Protein mor-promoting phorbol esters that mimic the structure of + IP3 ADP DAG have been shown to activate protein kinase C. They Intracellular ATP + can, therefore, bypass the receptor by passing through the calcium storage protein P_ plasma membrane and directly activating protein kinase C, sites causing the phosphorylation of downstream targets to re- Ca2+ Ca2+ sult in cellular proliferation. Biological IP promotes the release of calcium ions into the cyto- effects 3 Biological 2+ plasm by activation of endoplasmic or sarcoplasmic reticu- Ca effects lum IP3-gated calcium release channels (see Chapter 9). A, The pathway leading to the genera- most cells is in the range of 10 M. With appropriate stim- ulation, the concentration may abruptly increase 1,000 tion of inositol trisphosphate and diacylglycerol. The resulting increase in free cytoplasmic phosphorylation of phosphatidylinositol (PI) leads to the generation of phosphatidylinositol 4,5-bisphosphate (PIP2). Phospholipase C calcium synergizes with the action of DAG in the activa- (PLC) catalyzes the breakdown of PIP2 to inositol trisphosphate tion of some forms of protein kinase C and may also acti- (IP ) and diacylglycerol (DAG), which are used for signaling and 3 vate many other calcium-dependent processes. Mechanisms exist to reverse the effects of DAG and IP3 B, The generation of IP3 and DAG and their intracellular signaling by rapidly removing them from the cytoplasm. The binding of hormone (H) to a G-protein-coupled receptor dephosphorylated to inositol, which can be reused for phos- (R) can lead to the activation of PLC. The DAG is converted to phospha- Gq, a G protein that couples receptors to PLC.

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