Artane

By Y. Khabir. New Brunswick Theological Seminary.

D5 and the rat D1b are species homologs because they map to the same chromosomal locus (26) effective 2 mg artane kneecap pain treatment. D5 and D1b have a 10-fold higher affinity for dopamine purchase artane 2 mg fast delivery pain tailbone treatment, suggesting that D5 receptors are activated at neurotransmitter concentrations that are subthreshold for the D1 receptor (21). The D2-like receptors bind butyrophenones and benzamides with high affinity and bind benzazepines with low affinity (10,15,16). The pharmacological distinction of dopamine receptor subtypes holds tremendous potential for treatment of nervous system dysfunction. Dopamine receptors are the primary targets for the pharmacological treatment of PD, schizophrenia, and several other nervous system disorders. Presently used drugs have significant limitations that are in part due to their nonselective binding to many receptor subtypes. For example, drug-related side effects, including dyskinesias and delirium, are frequent and important problems in parkinsonian patients receiving levodopa or dopamine agonist therapy. These adverse effects result from stimulation of dopamine receptors in motor and cognitive circuits, respectively (21). Conversely, treatment of schizophrenia with dopaminergic antagonists, although intended to Copyright 2003 by Marcel Dekker, Inc. Clearly, drugs aimed at molecular subtypes of dopamine receptors offer the potential for specific therapeutic interventions for motor and psychiatric disorders of the nervous system. Although there are agonists and antagonists that are highly selective and that can discriminate between D1-like and D2-like receptor subfamilies, there are few agents that are highly selective for the individual receptor subtypes (Table 1). Some progress has been made in the development of antagonists for the D2 receptor family. For the D1/D5 receptor subtypes, there are currently no compounds that exhibit high selectivity. Thus, the high overall sequence homology between dopamine receptors of the same subfamily have made it difficult to develop specific ligands that do not interact with related receptors. The high affinity of the ‘‘atypical’’ neuroleptic, clozapine, for D4 receptors and the low level of D4 receptor expression in the striatum and high levels in the cerebral cortex and certain limbic brain areas led to the suggestion that the antipsychotic properties of the neuroleptics may be mediated through blockade of D4 receptors, whereas the side effects may be mediated through blockade of D2 receptors (15,60). This hypothesis was strengthened by the low incidence of extrapyramidal side effects for clozapine. However, clozapine at therapeutic doses also blocks many other types of receptors in addition to D4 receptors making it difficult to draw definitive conclusions. For example, clozapine binds to muscarinic acetylcholine receptors and is 20- to 50-fold more potent at these sites than at D2 receptors (for review, see Ref. By determining fractional occupancies of receptors bound by therapeutic drug levels, it has been demonstrated that the dominant factor for deciding if a particular antipsychotic drug will elicit parkinsonism is whether it binds more tightly or more loosely than dopamine at the D2 receptor subtype. Thus, for those antipsychotic drugs that elicit little or no parkinsonism, it appears that the high endogenous dopamine in the human striatum must outcompete the more loosely bound neuroleptic at the striatal D2 receptor subtype. Dopamine less readily displaces the more hydrophobic radioligands of the haloperidol type, providing an additional correlate between the magnitude of in vivo competition with endogenous agonists and parkinsonism. The separation of antipsychotic drugs into ‘‘loose’’ and ‘‘tight’’ binding to D2 receptors is consistent with the observation that catalepsy induced by olanzapine and loxapine (more loosely bound than Copyright 2003 by Marcel Dekker, Inc. T Properti es ofD opam i ne R eceptorS ubtypes D l e l e R eceptorsubtype A i no aci ds C h rom osom e q p q p p þ S econd esseng er cA P cA P cA P ch annel cA P K ch annel a ch annel ch annel C a m R S tri atu i ppocam pus K i dney S tri atu ucleus A ccu bens erebralcortex S electi v e ag oni sts S S rom ocri pti ne PA T — B utaclam ol Pram i pexole Perg oli de Perg oli de R opi ni role R opi ni role PD S electi v e antag oni sts S S S pi perone S pi perone S pi perone R aclopri de R aclopri de lozapi ne S ulpi ri de S ulpi ri de N afodotri de S ata from R efs. Taken together, these observations suggest that D2 blockade may be necessary for achieving antipsychotic action. This suggestion is in keeping with the observation that many patients will suddenly relapse when stopping clozapine, perhaps due to a sudden pulse of endogenous dopamine arising from emotional or physical activity which displaces the loosely bound neuroleptic from the receptor. Clinical dosing schedules can be adjusted to obtain sufficient but low occupancies of D2 receptors in order to minimize the development of parkinsonism. The psychosis caused by levodopa or bromocriptine can be readily treated by low doses of either clozapine or remoxipride (62), since there is very little endogenous dopamine to compete with the antagonist. Further studies are needed to determine whether newer antipsychotic drugs with low affinity for D2 receptors and with low risk for parkinsonism will cause less tardive dyskinesia.

Platelets do not have nuclei or DNA cheap 2mg artane otc sports spine pain treatment center westchester, but they do con- Platelets tain active enzymes and mitochondria generic artane 2 mg with amex acute chest pain treatment guidelines. The number of platelets in the circulat- ing blood has been estimated to range from 150,000 to 450,000 per L A Platelets B Megakaryocyte (mm3). Philadelphia: Lippincott Williams & Wilkins, agulation (clotting). Blood Clotting The fluid that remains after clotting has occurred is called serum (plural, sera). Serum contains all the com- The many substances necessary for blood clotting, or co- ponents of blood plasma except the clotting factors, as ex- agulation, are normally inactive in the bloodstream. A pressed in the formula: balance is maintained between compounds that promote clotting, known as procoagulants, and those that prevent Plasma serum clotting factors clotting, known as anticoagulants. In addition, there are Several methods used to measure the body’s ability to chemicals in the circulation that act to dissolve any un- coagulate blood are described later in this chapter. Under normal conditions, the substances that prevent clot- Checkpoint 13-11 What happens when fibrinogen converts to ting prevail. The clotting process is a well-controlled series of sep- arate events involving 12 different factors, each desig- nated by a Roman numeral. The final step in these reac- ◗ Blood Types tions is the conversion of a plasma protein called If for some reason the amount of blood in the body is se- fibrinogen (fi-BRIN-o-jen) into solid threads of fibrin, verely reduced, through hemorrhage (HEM-eh-rij) (ex- which form the clot. One possible measure to tion are described below and diagrammed in Figure 13-8: take in such an emergency is to administer blood from ◗ Substances released from damaged tissues result in the another person into the veins of the patient, a procedure formation of prothrombinase (pro-THROM-bih-nase), called transfusion. Care must be taken in transferring a substance that triggers the final clotting mechanism. Fibrin forms a network of threads that are said to be hemolyzed (HE-mo-lized), and the result- entraps plasma and blood cells to form a clot. Certain proteins, called antigens (AN-ti-jens) or ag- Blood clotting occurs in response to injury. Blood also glutinogens, on the surface of the red cells cause these in- clots when it comes into contact with some surface other compatibility reactions. There are many types of such than the lining of a blood vessel, for example, a glass or proteins, but only two groups are particularly likely to cause a transfusion reaction, the so-called A and B anti- gens and the Rh factor. Injury or removal of blood from vessels The ABO Blood Type Group There are four blood types involving the A and B antigens: Preliminary steps in clotting A, B, AB, and O (Table 13-3). These letters indicate the type of antigen present on the red cells. If only the A anti- Prothrombin gen is present, the person has type A blood; if only the B Prothrombinase Ca++ antigen is present, he or she has type B blood. Type AB red Thrombin cells have both antigens, and type O have neither. Of course no one has antibodies to his or her own blood type Fibrinogen Fibrin threads antigens, or their plasma would destroy their own cells. ZOOM- gens on the donor’s red cells to cause a transfusion reac- ING IN What material in the blood forms a clot? THE BLOOD 271 Table 13•3 The ABO Blood Group System BLOOD RED BLOOD REACTS WITH PLASMA CAN TAKE CAN TYPE CELL ANTIGEN ANTISERUM ANTIBODIES FROM DONATE TO A Anti-A Anti-B A, O A, AB B Anti-B Anti-A B, O B, AB AB A, B Anti-A, Anti-B None AB, A, B, O AB O None None Anti-A, Anti-B O O, A, B, AB Testing for Blood Type Blood sera containing anti- Anti-A serum Anti-B serum bodies to the A or B antigens are used to test for blood type. These antisera are prepared in animals using either the A or the B antigens to induce a response. Blood serum containing antibodies that can agglutinate and destroy red cells with A antigen is called anti-A serum; blood serum containing antibodies that can destroy red cells with B antigen is called anti-B serum. When combined with a blood sample in the laboratory, each antiserum Type A causes the corresponding red cells to clump together in a process known as agglutination (ah-glu-tih-NA-shun). The blood’s agglutination pattern when mixed separately with these two sera reveals its blood type (Fig. Type A reacts with anti-A serum only; type B reacts with anti-B serum only. Type AB agglutinates with both, and type O agglutinates with neither A nor B. Both the red cells and the serum are tested separately for any pos- sible cross-reactions with donor blood. Checkpoint 13-12 What are the four ABO blood type groups?

The cleavage of a high-energy phosphate bond in the nucleotide triphosphate and release of pyrophosphate (from the and phos- phates) provides the energy for this polymerization reaction purchase 2mg artane visa treatment for post shingles nerve pain. Subsequent cleavage of the pyrophosphate by a pyrophosphatase also helps to drive the polymerization reac- tion forward by removing a product cheap 2 mg artane fast delivery postoperative pain treatment guidelines. RNA polymerases must be able to recognize the startpoint for transcription of each gene and the appropriate strand of DNA to use as a template. They also must be sensi- tive to signals that reflect the need for the gene product and control the frequency of transcription. A region of regulatory sequences called the promoter, usually contiguous with the transcribed region, controls the binding of RNA polymerase to DNA and iden- tifies the startpoint (see Fig. The frequency of transcription is controlled by reg- ulatory sequences within the promoter, nearby the promoter (promoter-proximal ele- ments), and by other regulatory sequences, such as enhancers, that may be located at considerable distances, sometimes thousands of nucleotides, from the startpoint. Both the promoter-proximal elements, and the enhancers interact with proteins that stabilize RNA polymerase binding to the promoter. The -phosphate from the added nucleotide (shown in black) con- Ivy Sharer’s sputum stain suggested that nects the ribosyl groups. Rifampin inhibits bacterial RNA poly- Bacterial cells have a single RNA polymerase that transcribes DNA to generate all merase, selectively killing the bacteria that of the different types of RNA (mRNA, rRNA, and tRNA). The nuclear RNA poly- Escherichia coli contains four subunits ( 2 ), which form the core enzyme. Another protein called a (sigma) factor binds the core enzyme and directs bind- Although rifampin can inhibit the synthesis ing of RNA polymerase to specific promoter regions of the DNA template. The of mitochondrial RNA, the concentration factor dissociates shortly after transcription begins. In contrast to prokaryotes, eukaryotic cells have three RNA polymerases (Table Table 14. Polymerase I produces most of the rRNAs, polymerase II produces mRNA, and polymerase III produces small RNAs, such as tRNA and 5S rRNA. All of these RNA polymerases have the same mechanism of action. However, they recognize RNA polymerase I: RNA different types of promoters. RNA polymerase II: mRNA RNA polymerase III: tRNA other small RNAs A. Sequences of Genes Double-stranded DNA consists of a coding strand and a template strand (Fig. It is complementary and antiparallel both to the coding (nontemplate) strand of the DNA and to the RNA transcript produced from the template. Thus, the coding strand of the DNA is identical in base sequence and direction to the RNA transcript, except, of course, that wherever this DNA strand contains a T, the RNA transcript contains a U. By convention, the 240 SECTION THREE / GENE EXPRESSION AND THE SYNTHESIS OF PROTEINS The mushrooms picked by Amanda Tin contained -amanitin, an inhibitor of eukaryotic RNA polymerases. It is particularly effective at blocking the action of RNA polymerase II. This toxin initially causes gastrointestinal disturbances, then electrolyte imbalance and fever, followed by liver and kidney dysfunction. Between 40 and 90% of the individuals who ingest -amanitin die within a few days. OH H3 2OH CH H HN CH CO NH C CO NH CH2 CO OC H2C NH CH3 H CH O S N H H OH CH CH HO N CH CO 2 3 2 OC CH NH CO CH NH CO CH2 NH H2C CONH2 α–Amanitin nucleotide sequence of a gene is represented by the letters of the nitrogenous bases of the coding strand of the DNA duplex. It is written from left to right in the 5 to 3 direction. During translation, mRNA is read 5 to 3 in sets of three bases, called codons, that determine the amino acid sequence of the protein (see Fig. For this reason, when gene sequences are given, they refer to the coding strand. A gene consists of the transcribed region and the regions that regulate transcrip- tion of the gene (e. The base in the coding strand of the gene serving as the startpoint for transcription is numbered 1. This nucleotide corresponds to the first nucleotide incorporated into the RNA at the 5 -end of the transcript.