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For the other 4-TM domain receptors (and for those in the 3-TM domain and 2-TM domain families) the transmembrane topology of each subunit has been inferred by analogy with the nAChR discount 50 mg viagra soft free shipping erectile dysfunction drugs class, from hydropathicity analysis of the subunit amino-acid sequence (about 20 hydrophobic amino acids are needed to form an alpha- helix long enough to span the cell membrane) and from experiments manipulating recombinant receptor subunits buy viagra soft 50 mg cheap erectile dysfunction psychological causes treatment. All the 4-TM domain receptor subunits have both amino and carboxy terminals located on the outside of the membrane (Fig. In (a), the topology of the 4- TM domain subunits is illustrated embedded in the cell membrane. Receptors in this class are the nicotinic acetylcholine receptors, GABAA and GABAC receptors, glycine receptors and 5-HT3 receptors. Shown below is the likely pentameric stoichiometry of the 4-TM domain receptors with TM2 of each subunit lining the central ion channel. In (b), the transmembrane topology of the ionotropic glutamate receptors is shown. TM2 creates a pore-forming loop which penetrates into the cell membrane from the intracellular side. As illustrated below, the likely stoichiometry of the glutamate receptors is a tetramer. The exact contribution of TM1, TM3 or TM4 to forming the ion channel is uncertain. These subunits cross the cell membrane only twice and the ion channel is probably formed by a short polypeptide loop entering the membrane from the outside. The exact stoichiometry of the P2X receptors is uncertain but current evidence supports the suggestion that they are trimers agonist binding site is located in the amino terminal domain before the start of TM1 and the ion channel is formed by the TM2 domains of each subunit which come together to make up the complete receptor. Thus the amino acids in TM2 determine the ion conductance properties of the channel. For GABA and glycine receptors a Cl7 channel is formed while for the other ion channel receptors, the channel is largely cation non-selective for monovalent ions such as Na‡ and K‡ and is often also permeable to calcium. One of the key differences between different ion channel receptors for glutamate, ACh, 5-HT and ATP is in their relative permeability to calcium and this is controlled by the amino acids which line the ion channel. The ionotropic glutamate receptors (kainate, AMPA and NMDA) are formed by subunits which are predicted to cross the cell membrane three times (Fig. The ionotropic glutamate receptor subunits have a large extracellular amino terminal domain and a long intracellular carboxy terminal domain (Fig. The P2X receptor subunits are unusual in having only two transmembrane domains with both the amino terminal and carboxy terminal located intracellularly. The ion channel is proposed by analogy with the structure of some potassium channels to be formed by a short loop which enters the membrane from the extracellular side (North and Surprenant 2000). Subunit stoichiometry The ion channel receptors are multi-subunit proteins which may be either homomeric (made up of multiple copies of a single type of subunit) or heteromeric (composed of more than one subunit type). These subunits come together after synthesis in the endoplasmic reticulum to form the mature receptor. A receptor composed of two a and three b subunits is therefore denoted as having a stoichiometry of a2b3. This can cause confusion when related subunits are given sequential numbers: b1, b2, b3, etc. The convention is there- fore that subunits are numbered normally while stoichiometry is indicated by subscripts so that a pentamer of a4 and b3 subunits might have a stoichiometry of a42b33. NICOTINIC RECEPTORS All receptors in the 4-TM domain family are thought to form pentameric receptors in which five subunits (Fig. Their structure has been most extensively studied in the case of the nicotinic acetylcholine receptor (analogous to the muscle endplate receptor) from Torpedo electroplaque (Unwin 2000) where there is now a detailed knowledge of the receptor in both resting and active conformations. The muscle receptor has a subunit stoichiometry of two a subunits, providing the agonist binding sites, and three other subunits (b, g and d). In adult muscle an e subunit is present instead of the g subunit which is found in the foetal-type receptor. The five subunits are arranged like the staves of a barrel around the central channel.

Serotonergic neurons buy viagra soft 100 mg erectile dysfunction medication options, originating in the dorsal Raphe nucleus (DRN) viagra soft 50mg mastercard erectile dysfunction drugs mechanism of action, innervate both the amygdala and the PAG. In the former region, they are thought to augment active avoidance of aversive signals by exaggerating the amygdalar response to conditioned aversive stimuli (Deakin and Graeff 1991; Graeff et al. This response could be modulated, at the level of both the DRN and the amygdala, by neuronal inputs from both the frontal ANXIETY 417 Figure 19. Inputs from the behavioural inhibition system also augment the activity of the (ventromedial) hypothalamus which suppresses the flight/ fight response generated in the periaquaductal grey. In contrast, the amygdala inhibits hypothalamic activity and releases the flight/fight response. Anti-anxiety drugs are thought to inhibit monoaminergic activation of the behavioural inhibition system cortex, which is thought to process the perception of sensory information, and the hippocampus, which processes contextual (environmental) cues. Deakin and Graeff (1991) further propose the existence of a pathway, again arising in the DRN, which inhibits activation of the PAG. It is suggested that a reduction of serotonergic transmission in this area releases the flight/fight response. Under normal conditions, activity in this system is governed by higher centres in the forebrain (the cortex and hippocampus) so that, when interpretation of prevailing stimuli deems it appropriate, the flight/fight response is suppressed. A deficit in serotonergic inhibition of the PAG is thought to be the origin of panic. For instance, during low arousal states, a decline in the activity of forebrain serotonergic systems would diminish the inhibition of the PAG. This would ensure that threatening stimuli would evoke a protective escape response by default until cortical systems switch off the PAG response, if appropriate, as arousal increases (Handley 1995). It could also explain why patients often report that they are woken up during the night by their panic attacks. This system comprises the amygdala, hypothalamus and periaquaductal grey (PAG) and coordinates behavioural and neuroendocrine responses to conditioned and unconditioned aversive stimuli. Activity within the defence system is governed by higher centres, such as the frontal cortex and hippocampus. Serotonergic neurons projecting from the dorsal Raphe nucleus are proposed to activate the amygdala (‡) thereby promoting the response to conditioned aversive stimuli (anxiety). Projections from this nucleus to the dorsal and ventral periaquaductal grey (dPAG and vPAG) are thought to suppress (7) the flight/fight response to aversive stimuli. A deficit in serotonergic transmission to this brain region is thought to underlie panic. Possible targets for anti-anxiety drugs, acting via the GABAA receptor, are indicated by the dotted arrows. See text for further details There is a good deal of evidence that postsynaptic 5-HT2A/2C receptors mediate the actions of 5-HT in both the amygdala and the PAG (Deakin, Graeff and Guimaraes 1992). Thus local infusion of 5-HT2A/2C antagonists into the amygdala has an anti- conflict effect in animals while their systemic administration might have (albeit controversially) anti-anxiety effects in humans. In contrast, these drugs promote the flight/fight response to aversive stimuli. This leads to the prediction that drugs that relieve anxiety, through inhibition of 5-HT transmission in the amygdala, will exacerbate panic by inhibiting the restraining influence of 5-HT in the PAG. In fact, this has been offered as an explanation for the panic attacks experienced by some patients given buspirone. It could also explain the increase in panic attacks in the early stages of treatment with antidepressants. These drugs first decrease the firing rate of serotonergic neurons and the terminal release of 5-HT; recovery of neuronal firing and ANXIETY 419 increased release of 5-HT, like the relief of panic by these drugs, requires prolonged treatment (see Chapter 20). Obviously, any explanation of anxiety must account for the actions of benzo- diazepines. According to this scheme, benzodiazepines might activate this latter system and generate spurious safety signals (see Handley 1995).

The emergency room physician inserted a drainage tube into the left chest (into the pleural space) to treat the pneumothorax cheap viagra soft 100mg with mastercard erectile dysfunction treatment miami. Because of the finding of tenderness order viagra soft 50 mg free shipping erectile dysfunction vacuum, a peritoneal lavage was performed. This procedure involves penetrating the abdominal wall and inserting a tube into the peritoneal cavity. Clear fluid such as sterile water or normal saline is then instilled into the abdomen and siphoned out again. A return of lavage fluid containing blood, fecal matter, or bile indicates injury to an abdominal organ that requires surgery. However, the nurse stated that lavage fluid was draining out of the chest tube. From what you know about how the various body cavities are organized, do you suppose FIGURE: Radiographic anatomy is this phenomenon could be explained based on normal anatomy? What might have caused it to important in assessing trauma to bones and occur in our patient? If it does not, explain why in terms of the relationship of the various organs to the membranes within the abdomen. Body Organization and © The McGraw−Hill Anatomy, Sixth Edition Organization, and the Anatomical Nomenclature Companies, 2001 Human Organism Chapter 2 Body Organization and Anatomical Nomenclature 23 Notochord Dorsal hollow CLASSIFICATION AND nerve cord Primitive eye CHARACTERISTICS OF HUMANS Humans are biological organisms belonging to the phylum Chor- data within the kingdom Animalia and to the family Hominidae within the class Mammalia and the order Primates. Objective 2 List the characteristics that identify humans as chordates and as mammals. Pharynx Objective 3 Describe the anatomical characteristics that set Pharyngeal humans apart from other primates. Our scientific name translates Umbilical bud cord from the Latin to “man the intelligent,” and indeed our intelli- gence is our most distinguishing feature. It has enabled us to Limb bud build civilizations, conquer dread diseases, and establish cultures. We have invented a means of communicating through written Creek symbols. We record our own history, as well as that of other or- ganisms, and speculate about our future. The ever more ingenious ways for adapting to our changing environ- three diagnostic chordate characteristics are indicated in boldface type. At the same time, we are so intellectually specialized that we are not self-sufficient. We need one another as much as we need the recorded knowledge of the past. We are constantly challenged to learn more about our- ferred to as a taxon. As we continue to make new discoveries about our struc- most specific taxon is the species. Humans are species belonging ture and function, our close relationship to other living organisms to the animal kingdom. Phylogeny (fi-loj′˘-nee ) is the science that becomes more and more apparent. Often, it is sobering to realize studies relatedness on the basis of taxonomy. As human organisms, we breathe, eat and digest food, excrete bodily Phylum Chordata wastes, locomote, and reproduce our own kind. These chordate characteristics are development is found throughout nature. The fundamental pat- well expressed during the embryonic period of development and, terns of development of many nonhuman animals also characterize to a certain extent, are present in an adult. Recent genetic mapping of flexible rod of tissue that extends the length of the back of an the human genome confirms that there are fewer than 35,000 embryo. A portion of the notochord persists in the adult as genes accounting for all of our physical traits. By far the majority the nucleus pulposus, located within each intervertebral disc of these genes are similar to those found in many other organisms. The dorsal hollow nerve cord is positioned above the In the classification, or taxonomic, system established by notochord and develops into the brain and spinal cord, which biologists to organize the structural and evolutionary relation- are supremely functional as the central nervous system in the ships of living organisms, each category of classification is re- adult.

Transport of tryptophan across the blood±brain barrier and neuronal membranes relies on a specific carrier for large neutral amino acids (LNAAs) purchase viagra soft 100 mg mastercard cough syrup causes erectile dysfunction. Thus purchase viagra soft 50mg line erectile dysfunction young age causes, although an increase in the relative concentration of plasma tryptophan, either through dietary intake or its reduced metabolism in a diseased liver, increases its transport into the brain, other LNAAs (such as leucine, isoleucine or valine) can compete for the carrier. It is known that consumption of carbohydrates increases secretion of insulin which, in addition to its well-known glucostatic role, promotes uptake of LNAAs by peripheral tissues. However, it seems that tryptophan is less affected by insulin than the other LNAAs in this respect and so its relative concentration in the plasma increases, thereby increasing its transport into the brain (see Rouch, Nicolaidis and Orosco 1999). The resulting increase in synthesis and release of 5-HT is claimed to enhance mood. Although this scheme is rather controversial, it has been suggested as an explanation for the clinical improvement in some patients, suffering from depression or premenstrual tension, when they eat carbohydrates. It has also been suggested to underlie the carbohydrate-craving experienced by patients suffering from Seasonal Affective Disorder (Wurtman and Wurtman 1995). Not a great deal is known about factors that actually activate tryptophan hydroxylase. In particular, the relative contribution of tryptophan supply versus factors that specifically modify enzyme activity under normal dietary conditions is unknown. However, removal of end-product inhibition of tryptophan hydroxylase has been firmly ruled out. Also, it has been established that this enzyme is activated by electrical stimulation of brain slices, even in the absence of any change in tryptophan concentration, and so other mechanisms are clearly involved. So far, it has been established from in vitro studies that the enzyme undergoes phosphorylation, a process that changes the conformation of the enzyme protein and leads to an increase in its activity. This involves Ca2‡/calmodulin-dependent protein kinase II and cAMP-dependent protein kinase which suggests a role for both intracellular Ca2‡ and enzyme phosphorylation in the activation of tryptophan hydroxylase. Indeed, enzyme purified from brain tissue innervated by rostrally projecting 5-HT neurons, that have been stimulated previously in vivo, has a higher activity than that derived from unstimulated tissue but this increase rests on the presence of Ca2‡ in the incubation medium. Also, when incubated under conditions which are appropriate for phosphorylation, the Km of tryptophan hydroxylase for its co-factor and substrate is reduced whereas its Vmax is increased unless the enzyme is purified from neurons that have been stimulated in vivo, suggesting that the neuronal depolarisation in vivo has already caused phosphorylation of the enzyme. This is supported by evidence that the enzyme activation caused by neuronal depolarisation is blocked by a Ca2‡/calmodulin protein kinase inhibitor. However, whereas depolarisation 5-HYDROXYTRYPTAMINE 193 alone increases enzyme Vmax, it does not appear to affect the enzyme Km and so a firm link between neuronal depolarisation and enzyme phosphorylation has yet to be established. The apparent reliance of enzyme activation on phosphorylation and intracellular Ca2‡ gives a clue as to how the rate of 5-HT synthesis might be coupled to its impulse- evoked release. Certainly, the impulse-induced increase in intracellular Ca2‡, and/or activation of the G protein-coupled receptors that govern synthesis of cAMP, could modify the activity of tryptophan hydroxylase. Indeed, this could explain why activation of either somal 5-HT1A autoreceptors in the Raphe nuclei (which depress the firing rate of 5-HT neurons) or terminal 5-HT1B autoreceptors (which depress 5-HT release) can reduce the production of cAMP and attenuate 5-HT synthesis. The product of the hydroxylation of tryptophan, 5-hydroxytryptophan, is rapidly decarboxylated to 5-HT by a specific decarboxylase enzyme. This is generally thought to be a soluble enzyme which suggests that 5-HT is synthesised in the cytoplasm, before it is taken up into the storage vesicles. If this is the case, then considerable losses might be incurred from its metabolism by monoamine oxidase before it reaches the storage vesicles. Indeed, this could explain why 5-HT turnover seems to greatly exceed its rate of release. The high affinity of the decarboxylase enzyme for its substrate (10 mM in the brain) makes it unlikely that this stage could ever become rate-limiting for the pathway as a whole. Nevertheless, the Km for this enzyme is considerably higher than tissue concentrations of 5-hydroxytryptophan and so, again, supply of this substrate is likely to be a crucial factor. Finally, as with the noradrenergic system, there is evidence for long-term changes in the rate of synthesis of 5-HT that are triggered by prolonged changes in its rate of release. It has even been shown that mRNA for tryptophan hydroxylase shows a daily rhythm in cultured eye-cups maintained in the dark. Again, not a great deal is known about the underlying control mechanisms but the synthesis of tryptophan hydroxylase, at least, is increased by exposure of 5-HT neurons in vivo to the growth factor, brain-derived neurotrophic factor (`BDNF; Siuciak et al. Steroid hormones also seem to modulate tryptophan hydroxylase gene transcription but research in this area is confounded by the variation in this effect across different tissues and different hormones, with both increases and decreases being reported. In fact, three such proteins have now been characterised, but only one of them, 45 kDa SBP, appears to be secreted into the synapse along with 5-HT. Whether they serve any role other than forming an osmotically inert storage matrix for 5-HT is unknown.