By H. Mojok. University of Missouri-Columbia.
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Other kinases buy 100 mg tegretol with amex muscle relaxant johnny english, such as the GPCRs resolved by gel electrophoresis can also be ana- 3′ discount 400mg tegretol free shipping spasms near gall bladder,5′-cyclic adenosine monophosphate (cAMP)-dependent lyzed by chemical sequencing, typically by a process called protein kinase (PKA) and protein kinase C can also regulate Edman degradation, which sequentially cleaves residues GPCRs by phosphorylating distinct cytoplasmic serine/ from the amino-terminal end of the protein. A very powerful method for phorylated by other kinases, such as GRKs, are more diffi- determining amino acid sequence and detecting posttransla- cult to predict because they do not conform to a rigidly tional modifications of proteins is via mass spectrometric defined consensus sequence. For example, with tandem mass spectrometry it is enzymes with relatively well-understood substrate specificity possible to measure the mass of specific protein fragments in vitro, there are major limitations to the use of sequence with an accuracy of one part in 10,000 up to 12,000 daltons analysis for predicting phosphorylation sites in vivo. The impressive dues conforming to a specific consensus sequence are not accuracy of this method makes it possible to detect phos- always phosphorylated under physiologic conditions, and, phorylation as well as many other posttranslational modifi- conversely, in some cases residues that do not conform to cations, even those that cause subtle changes in the protein a well-defined consensus sequence can be phosphorylated size or charge. Thus it is important to determine the Chromatography, which refers to any separation based phosphorylation of GPCRs when expressed in the appropri- on differential behavior of a molecule between a stationary ate mammalian cells. High-performance liquid chroma- tography (HPLC) using reverse-phase (e. By compar- There are many ways of detecting phosphorylated proteins. Subsequently, these fragments can be isolated and fur- PAGE, proteins dissolved in SDS are loaded onto one end ther analyzed by methods such as Edman degradation or of a porous gel and exposed to an electric field, which causes mass spectrometry. By using Methods to Examine Regulation of appropriate radiolabeled compounds (such as inorganic Receptors byLocalization and Trafficking phosphate added to the culture medium), it is possible to apply the technique of autoradiography to specifically detect It has been appreciated for many years that a critical parame- radioactive, phosphorylated proteins resolved by SDS- ter that can regulate the strength of functional signal trans- PAGE. It is also possible to use gel electrophoresis to sepa- duction via GPCRs is the actual number of receptors present rate proteins according to relative charge, a property that in target tissues and, in particular, the number of receptors is modified predictably by certain modifications such as present in the plasma membrane of individual cells. These types of separation can be com- disturbances in the regulation of receptor number and/or bined in the use of two-dimensional gel electrophoresis, distribution may be of primary importance in the patho- 22: G-Protein–Coupled Receptors 283 physiology of certain neuropsychiatric disorders. For exam- which antibodies recognizing the native receptor are not ple, long-term administration of dopamine receptor antago- available. In either case the general scheme is as follows: nists can induce upregulation of specific receptors, which Cells or tissues expressing the receptor of interest are fixed may contribute to the apparent supersensitivity of dopamine using standard histologic methods. The fixed cells or tissue receptors associated with tardive dyskinesia (46). This phenomenon is termed bodies recognizing the receptor of interest. Studies using ra- tive epitopes in the specimen (typically several hours), the dioligand binding and subcellular fractionation techniques specimens are washed extensively to remove nonspecifically provided early evidence that multiple mechanisms are capa- associated antibodies. The directly visualizing the subcellular localization of GPCRs secondary antibody is typically coupled to a fluorochrome and for performing biochemical studies of specific receptor (such as fluorescein), a recognizable particle (such as colloi- trafficking mechanisms. GPCRs can be detected in situ in cell or tissue preparations using immunochemical techniques and receptor-specific an- Biochemical Methods to AssaySpecific tibodies. Antibodies that recognize the native receptor pro- Receptor Trafficking Processes tein can be used to examine the localization of endogenously expressed receptors, whereas epitope-tagging methods (see Whereas microscopic imaging can readily provide a great above) can be used to detect mutated versions of the receptor deal of qualitative information about GPCR localization protein or as a means to detect recombinant receptors for and trafficking, it can be quite challenging to quantitiate A B FIGURE 22. Visualization of HA epitope-tagged dopamine D1 receptors in transfected cells, using a fluorochrome-labeled secondary antibody and fluorescence microscopy. The ability of this receptortoundergoregulatedinternalizationis indicatedbythedopamine-inducedredistribution of immunoreactive receptors from the plasma membrane (visualized as linear staining at the cell periphery) to endocytic vesicles (visualized as punctate structures located throughout the cytoplasm). In addition to being extremely a specific subcellular localization or to measure accurately useful for examining posttranslational modifications of the rate or extent of specific trafficking processes. The im- GPCRs, in some cases it is possible to use these techniques portance of these processes has motivated the development to isolate receptor-containing complexes that presumably of biochemical methods for examining GPCR trafficking. The In addition to their utility for receptor localization, antibod- basic idea is to immunopurify a specific GPCR from cell ies specifically recognizing GPCRs facilitate biochemical or tissue extracts (or from a partially purified subcellular studies of GPCR trafficking using techniques adapted from fraction prepared from a cell or tissue lysate) using an anti- other areas of cell and molecular biology. For example, one body recognizing the native receptor or an engineered epi- method that has been extremely useful for quantitative stud- tope tag, and then to analyze proteins specifically associated ies of GPCR endocytosis is cell-surface biotinylation cou- with this complex using a different antibody. In general, pled with immunoprecipitation of receptors. Proteins pres- this is accomplished by immunoprecipitation of the receptor ent in the plasma membrane of cells can be specifically followed by analysis of associated proteins in the complex labeled by incubating intact cells in the presence of biotin by immunoblotting with the appropriate additional anti- coupled to an activated ester, which is membrane-imper- body. In some cases, the protein complexes are sufficiently meant and therefore forms a covalent bond only with ex- stable that they remain associated through the initial immu- posed amine moieties present in plasma membrane proteins. In other cases this is not true, In general, biotinylation in this manner does not adversely and the complexes dissociate before the receptor can be affect GPCR function, allowing biotinylation to be used as purified from the extract. In this case, various chemical a chemical tag for surface receptors. Using variations of this basic biochemistry, it is possi- teraction with heterotrimeric G proteins (52) and with - ble to measure a wide variety of membrane trafficking pro- arrestins (53), and to examine the regulation of these protein cesses. For example, internalization of GPCRs has been interactions by ligand-induced activation of the receptor. Recent studies provide strong support for this idea and, specifically, provide evidence for homo- and heterodimeri- Methods for Examining Specific Protein zation of individual GPCRs in vivo. This principle is per- Interactions Involved in GPCR Function haps best established for receptor tyrosine kinases, where it and Regulation is well established that oligomerization of receptors is re- A salient lesson emerging from recent cell biological studies quired for appropriate ligand-dependent signal transduction is that GPCR signal transduction can be viewed, in essence, (54). A relatively early hint that GPCRs may also undergo as a dynamically regulated network of protein–protein in- oligomerization came from studies of the 2-adrenergic re- teractions that occur in specific subcellular locations. There- ceptor using epitope-tagging techniques, where it was ob- fore, an important goal of current and future research is to served that receptors tagged with one epitope could specifi- define these critical protein interactions and elucidate their cally coimmunoprecipitate receptors tagged with a distinct temporal and spatial regulation in intact cells and tissues.
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Ultrasounds are cyclic sound pressures with a frequency above those which humans can hear cheap tegretol 400 mg line spasms neck. Ultrasounds used in the medical setting have a frequency of 1 to 25 mHz generic 200mg tegretol with visa quick spasms in lower abdomen. Sound waves are not ionising and are not harmful at the energy levels used for diagnostic purposes. There is to date no epidemiological evidence of harmful effects (Moore 2011). Ultrasounds travel faster in dense bodies and slower in compressible bodies. In soft tissue the speed of sound is 1540 m/s, in bone about 3400 m/s, and in air 330 m/s. In tissues where the sound travels more slowly, the wavelength decreases. Medical ultrasound waves are produced by a piezoelectric crystal as a consequence of the mechanical response to an electric field. The transducer also picks up the reflected waves or “echoes” from the tissues and converts them into electrical signals that are used to form real-time images on a computer. The crystal thus both transmits and receives the sound (Figure 2. From top to bottom: linear 10 and 18 and convex 5 mHz transducers. Each electric signal is registered, amplified, and filtered to reduce noise, and the depth of the tissue that has generated the echo is calculated. The signals are then digitalized and processed in order to produce an image. Ultrasound and Regional Anesthesia | 27 Early ultrasound devices used a single crystal to create a one dimension image, called a-mode image. Modern machines generate a b-mode or two-dimensional or gray-scale image created by 128 or more crystals. Each crystal receives a pulse that produces a scan line used to create an image on the screen. This image is renewed several times each second to produce a real-time image. Additional modes, including high resolution real time gray scale imaging, Doppler mode, color-flow Doppler mode, color-velocity Doppler and tissue harmonic modes are now commonly available. At the interface where one tissue borders another tissue, the wave is refracted and reflected back as an echo. The reflection depends on the tissue density and thus on the speed of the wave. So, as the waves penetrate tissues, they detect where soft tissue meets air, or soft tissue meets bone, or where bone meets air. Instead, some structures will completely absorb the sound waves. Thus, echoic tissues are those tissues that reflect the wave whereas anechoic tissues do not reflect the wave. Ultrasounds penetrate well through fluids that are anechoic and appear as black on the monitor. Fluids allow ultrasounds to pass through more or less attenuated until they encounter the surface of denser structures. Bone or air are poorly penetrated by ultrasounds and generate a kind of “sound-shadow”. The transverse appearance of nerves is round or oval and hypo-echoic (Figure 2. They may appear as honeycomb structures containing hyper-echoic points or septa inside them. Nerves are surrounded by a hyper-echoic border that corresponds to connective tissue. On the longitudinal scan, tendons disappear while 28 | Ultrasound Blocks for the Anterior Abdominal Wall tracking them for some distances whereas nerves do not disappear. Blood vessels appear as round hypo-echoic structures with a well defined hyper-echoic border corresponding to the vessel wall. The arteries are not compressible and are pulsating, veins have a thinner border and are compressible (Figure 5. Muscles appear as heterogeneous or homogeneous hypo-echoic structures with hyper-echoic septa and a fibrous-lamellar texture (Figure 3. The periostium appears as hyper-echoic as it reflects entirely the echoes. As a consequence, the bone underlying the periostium appears as black (ultrasound shadow) (Figure 4. The knowledge of normal anatomy is essential for the identification of different tissues with ultrasounds.