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PubMed1987

Structural and antigenic characterization of a species- and promastigote-specific Leishmania mexicana amazonensis membrane protein.

A Leishmania mexicana amazonensis promastigote membrane glycoprotein (Mr 46,000) expressing the species-specific and promastigote-specific epitope of monoclonal antibody IX 2H7-E10(M-2) has been purified to homogeneity, and studies have been made to determine the minimum peptide fragment that retained antigenic activity. Peptide mapping experiments performed with the metabolically labeled or surface radioiodinated protein illustrated its highly folded nature and marked resistance to proteolytic digestion. The M-2 epitope was readily destroyed by limited proteolysis and/or reduction and alkylation, indicating disulfide bond involvement in its formation by at least the secondary protein structure. The stability of approximately half of the molecular mass of the protein (46kDa/M-2) was also dependent on disulfide bonding. Enzymic digests under various conditions generated a glycopolypeptide (Mr 22,000 to 27,000), extremely resistant to further enzymic digestion, that was the dominant immunogenic portion of the purified protein recognized by a specific rabbit heteroserum. No smaller or larger fragments were antigenic. Data obtained by using the radioiodinated hydrophobic probe 3-(trifluoromethyl)-3-([m-125]iodophenyl)-diazirine ([125I]TID) indicate that 46kDa/M-2 is an integral membrane protein with a component polypeptide (Mr 23,000 to 27,000), highly resistant to further enzymic cleavage and containing sequences within the external promastigote membrane. Data indicate that the [125I]TID-labeled fragment is identical to the immunodominant fragment. We suggest that hydrophobic interactions maintain the integrity of this fragment as amino acids within it fold through the parasite membrane.

Amino Acids↗

PubMed2006

[Integration of genetic factors into epidemiological studies].

During the last two decades, genetic epidemiology has been established in parallel to the area of classical epidemiology. This paper presents some essentials of the epidemiology of genetic factors. It begins with a discussion of complex diseases that are characterized by an involvement of several genes. The problems that are attached to modeling gene-gene and gene-environment interactions and their integration into causal pathways are elucidated and the role of genetic factors in the etiology of complex diseases is investigated. Classical and new epidemiological study designs that allow an integration of genetic data are introduced. The introduction of this data is partly motivated by the danger of bias due to genetic heterogeneity (population stratification) in classical designs. The problem of replication of study results is discussed and the concept of Mendelian randomization is presented.

Case-Control Studies↗

PubMed1999

Role of TNF-alpha in local surgical trauma-induced microvascular dysfunction.

BACKGROUND/AIM: The aim of this study was to gain insight into the mechanisms of microvascular dysfunction after local surgical trauma. METHODS: The effect of anti-tumor necrosis factor (TNF)-alpha antibody (Ab) on microvascular function, including arteriolar diameter response, nutritive perfusion, leukocyte-endothelial cell interaction and endothelial integrity disruption, was studied in hamster skinfold chamber preparations using intravital fluorescence microscopy. RESULTS: Directly after the surgical procedure, arteriolar diameters were found to be markedly (p < 0.05) reduced, but recovered significantly at 8 h and reached plateau levels after 24 h. Surgical trauma further induced a strong inflammatory response characterized by a significant (p < 0.05) increase in leukocyte adherence to the endothelium of postcapillary venules. This inflammatory response was associated with an increase in microvascular permeability, indicating endothelial integrity disruption. Anti-TNF-alpha Ab had no significant effect on the surgical trauma-induced arteriolar vasomotor dysfunction; however, it effectively (p < 0.05) reduced venular leukocyte adherence and attenuated the increase in microvascular permeability. CONCLUSION: Our study indicates that arteriolar constriction, leukocyte-endothelial cell interaction and endothelial macromolecular leakage have to be considered as the characteristic microvascular response after local surgical trauma. It is conceivable that TNF-alpha plays a role in mediating the inflammatory response, but not the dysfunction of vasomotor control.

Animals↗

PubMed1994

Interaction between peroxidase and cyclooxygenase activities in prostaglandin-endoperoxide synthase. Interpretation of reaction kinetics.

Prostaglandin-endoperoxide synthases have two distinct enzymatic activities in the biosynthesis of prostanoids: a peroxidase and a fatty acid oxygenase. Hydroperoxides, such as the cyclooxygenase reaction product, prostaglandin G2, act both as substrates for the synthase peroxidase and as obligatory initiators of the cyclooxygenase reaction itself. A mechanistic scheme was devised to describe the interactions between the two activities of the synthase. This mechanism was based on a heme-dependent peroxidase mechanism such as that observed with horseradish peroxidase and initiation of the cyclooxygenase reaction by intramolecular reaction with a peroxidase intermediate. Rate equations derived from the mechanism were numerically integrated by an interactive computer program that consolidated the diverse phenomena to provide quantitative predictions of the reaction kinetics of the synthase. The predictions agreed well with experimental observations of the purified ovine seminal vesicle enzyme under a wide variety of conditions, including inhibition by exogenous hydroperoxide scavenger and by cyanide, stimulation by exogenous hydroperoxide, and inhibition of eicosapentaenoic acid oxygenation under conditions where arachidonic acid reacts rapidly. The detailed analyses of reaction kinetics made possible with the computer simulation provide important insights into the interactions between the two catalytic activities of the synthase in the control of prostaglandin biosynthesis.

Cyanides↗

PubMed1997

Prevention of pancreatic islet xenograft rejection by dietary vitamin E.

In pancreatic islet transplantation, the adhesion of activated leukocytes to endothelial cells and the loss of microvascular integrity represent the critical microcirculatory events, which promote loss of graft function due to rejection. With the view that oxygen radicals may contribute to graft rejection, we studied the effect of the antioxidant vitamin E on microvascular rejection of islet grafts. Islets were transplanted syngeneically and xenogeneically (rat) into dorsal skin-fold chambers of hamsters, which received a non-vitamin-E-supplemented laboratory chow. Treated animals with xenografts were fed with a diet supplemented with vitamin E in a low (150 mg/kg) and high (8000 mg/kg) concentration. Intravital fluorescence microscopy demonstrated complete vascularization of syngeneic grafts at day 10 after transplantation, intact islet microcirculation at day 20 with a functional capillary density of 653 +/- 6 cm-1, and only few leukocytes adherent to the endothelial lining of the islets' microvasculature (88 +/- 23 mm-2). Xenogeneic islets showed initial signs of rejection at day 6, including adhesion of leukocytes to the microvascular endothelium (610 +/- 110 mm-2) and loss of endothelial integrity. After 20 days, functional capillary density was significantly lower (173 +/- 68 cm-1) when compared with syngeneic grafts, indicating failure of graft acceptance. Supplementation of the diet with low and high concentrations of vitamin E resulted in a significant (P < 0.05) reduction of xenograft leukocyte-endothelium interaction (146 +/- 29 mm-2 and 109 +/- 42 mm-2) at day 6 after transplantation and and adequate development of functional capillary density at day 20 (478 +/- 36 cm-1 and 539 +/- 86 cm-1; P < 0.05), indicating prevention of microvascular rejection. We conclude that dietary supplementation of the lipophilic antioxidant vitamin E attenuates leukocyte-endothelial cell interactions, preserves microvascular integrity, and thus inhibits microvascular rejection in a dose-dependent fashion. Our study underscores the pivotal mediator role of reactive oxygen species in islet xenograft rejection and, furthermore, suggests that dietary vitamin E may act as an adjunct anti-rejection treatment in clinical islet transplantation.

Animals↗

PubMed1991

A software system for interactive and quantitative visualization of multidimensional biomedical images.

A comprehensive software system called ANALYZE has been developed which permits detailed investigation and evaluation of 3-D biomedical images. The software can be used with any 2-D or 3-D imaging modality, including x-ray computed tomography, radionuclide emission tomography, ultrasound tomography, magnetic resonance imaging and both light and electron microscopy. The package is unique in its synergistic integration of fully interactive modules for direct display, manipulation and measurement of multidimensional image data. Several original algorithms are included which improve image display efficiency and quality. One of the most versatile and powerful algorithms is interactive volume rendering, which is optimized to be fast without compromising image quality. An important advantage of this technique is to display 3-D images directly from the original data and to provide on-the-fly combinations of selected image transformations and/or volume set operations (union, intersection, difference, etc.). The inclusion of a variety of interactive editing and quantitative mensuration tools significantly extends the usefulness of the software. Any curvilinear path or region-of-interest can be manually specified and/or automatically segmented for numerical determination and statistical analyses of distances, areas, volumes, shapes, densities and textures. ANALYZE is written entirely in "C" and runs on several standard UNIX workstations. It is being used in a variety of applications by over 40 institutions around the world, and has been licensed by Mayo to several imaging companies. The software architecture permits systematic enhancements and upgrades which has fostered development of a readily expandable package. ANALYZE comprises a powerful "visualization workshop" for rapid prototyping of specific application packages, including applications to interactive surgery simulation and radiation treatment planning. ANALYZE offers the potential to accurately and reproducibly examine, from images, the structure and function of any cell, tissue, limb, organ or organ system of the body, much like a surgeon or pathologist might do in real life, but entirely non-invasively, without pain or destruction of tissue. These capabilities promise exciting new insights into the basic processes of life, and major advances in health care delivery through improved diagnosis and treatment of disease.

Computer Graphics↗

PubMed2006

Predator functional response and prey survival: direct and indirect interactions affecting a marked prey population.

1. Predation plays an integral role in many community interactions, with the number of predators and the rate at which they consume prey (i.e. their functional response) determining interaction strengths. Owing to the difficulty of directly observing predation events, attempts to determine the functional response of predators in natural systems are limited. Determining the forms that predator functional responses take in complex systems is important in advancing understanding of community interactions. 2. Prey survival has a direct relationship to the functional response of their predators. We employed this relationship to estimate the functional response for bald eagle Haliaeetus leucocepalus predation of Canada goose Branta canadensis nests. We compared models that incorporated eagle abundance, nest abundance and alternative prey presence to determine the form of the functional response that best predicted intra-annual variation in survival of goose nests. 3. Eagle abundance, nest abundance and the availability of alternative prey were all related to predation rates of goose nests by eagles. There was a sigmoidal relationship between predation rate and prey abundance and prey switching occurred when alternative prey was present. In addition, predation by individual eagles increased as eagle abundance increased. 4. A complex set of interactions among the three species examined in this study determined survival rates of goose nests. Results show that eagle predation had both prey- and predator-dependent components with no support for ratio dependence. In addition, indirect interactions resulting from the availability of alternative prey had an important role in mediating the rate at which eagles depredated nests. As a result, much of the within-season variation in nest survival was due to changing availability of alternative prey consumed by eagles. 5. Empirical relationships drawn from ecological theory can be directly integrated into the estimation process to determine the mechanisms responsible for variation in observed survival rates. The relationship between predator functional response and prey survival offers a flexible and robust method to advance our understanding of predator-prey interactions in many complex natural systems where prey populations are marked and regularly visited.

Animals↗

PubMed2004

Emotional competence as antecedent to performance: a contingency framework.

Emotional intelligence is the ability to monitor one's own and others' thinking and actions. In this integrative review, the author seeks to determine the causes of the weak relationship between emotional intelligence and performance by positing that certain emotional competencies, rather than emotional intelligence, are the true predictors of performance. The author theorizes that emotional competencies (including self-control, resilience, social skills, conscientiousness, reliability, integrity, and motivation) interact with organizational climate and job demands or job autonomy to influence performance, as represented in the form of 5 empirically testable propositions. Self-control and emotional resilience are considered to delay the onset of a decline in performance from excessive job demands. Social skills, conscientiousness, reliability, and integrity assist to promote trust, which in turn may build cohesiveness among the members of work groups. Motivation may fuel job involvement in environments that promise psychological safety and psychological meaningfulness. A combination of superior social skills and conscientiousness may enhance the self-sacrifice of benevolent employees to heightened levels of dependability and consideration. Finally, emotional honesty, self-confidence, and emotional resilience can promote superior performance, if positive feedback is delivered in an informative manner, and can mitigate the adverse effects of negative feedback.

Affect↗

PubMed1982

Stereotactic neurosurgery using 3-D image data from computed tomography.

During the last decade computer tomography (CT) scanners have provided images that show internal anatomy of unsurpassed resolution and that, since they are inherently digital, a format computer graphics software can easily process. By combining CT images, a specially designed head-mounted instrument, and the software to coordinate them, improved surgical accuracy can result for stereotactic surgery. Using the head-mounted frame and the interactive computer software described here, the entire stereotactic approach is transportable to computer systems of three major CT manufacturers. Neurosurgeons now have a tool that allows trajectory selection and probe placement entirely within the CT suite. Compared with conventional stereotaxis, the CT-aided approach offers increased accuracy, with a significant fluid contrast injection for finding reference points and the avoidance of important brain structures due to the direct visualization afforded with CT. Key interactive features are shown here that allow unrestricted views of anatomy in the area of surgical interest. For example, oblique views that are normal to the trajectory of neurosurgical instruments are extracted in real time during the surgical procedure. Standard sagittal (lateral) and coronal (frontal) image planes are also shown integrated with the interactive technique. The surgical procedure is outlined and details of the pattern recognition technique for image-to-frame registration are presented. Test, phantom, and patient results are given.

Brain↗

PubMed1998

Relationship between facilitation at threshold and suprathreshold contour integration.

We reevaluate the facilitation at threshold previously reported between aligned micropatterns and assess the role of such lateral spatial interactions in suprathreshold contour integration tasks. Contrary to previous claims, we show that these interactions are phase dependent. Furthermore, they are clearly evident only for foveal viewing, are not evident for curved alignments (> 20 degrees), and do not produce any suprathreshold consequence for contrast perception. Such findings question their usefulness for contour integration of smoothly curved suprathreshold paths.

Form Perception↗

PubMed1999

Individual hydrogen bonds play a critical role in MHC class II: peptide interactions: implications for the dynamic aspects of class II trafficking and DM-mediated peptide exchange.

Determination of the crystal structure of class II: peptide complexes has shown that in addition to pocket interactions involving the side chains of the peptide, peptide binding to MHC class II molecules is characterized by a series of hydrogen bonds which are contributed by genetically conserved amino acid residues in the class II molecule to the main chain of the peptide. Our experiments have revealed an unexpectedly large contribution of hydrogen bonds at the periphery of the MHC peptide binding pocket to MHC class II function. Kinetic studies have shown that peptide dissociation rates are profoundly accelerated by loss of a single hydrogen bonding residue. The magnitude of the effects seen with the loss in potential for a single hydrogen bond support a co-operative model in which individual bonds between class II and peptide are dependent on the integrity of neighboring interactions. Collectively our studies have revealed that MHC class II structure, peptide binding and intracellular trafficking events are critically dependent on the integrity of the hydrogen bonding network between class II molecules and its bound peptide.

Animals↗

PubMed1999

The induction of pain: an integrative review.

The highly disagreeable sensation of pain results from an extraordinarily complex and interactive series of mechanisms integrated at all levels of the neuroaxis, from the periphery, via the dorsal horn to higher cerebral structures. Pain is usually elicited by the activation of specific nociceptors ('nociceptive pain'). However, it may also result from injury to sensory fibres, or from damage to the CNS itself ('neuropathic pain'). Although acute and subchronic, nociceptive pain fulfils a warning role, chronic and/or severe nociceptive and neuropathic pain is maladaptive. Recent years have seen a progressive unravelling of the neuroanatomical circuits and cellular mechanisms underlying the induction of pain. In addition to familiar inflammatory mediators, such as prostaglandins and bradykinin, potentially-important, pronociceptive roles have been proposed for a variety of 'exotic' species, including protons, ATP, cytokines, neurotrophins (growth factors) and nitric oxide. Further, both in the periphery and in the CNS, non-neuronal glial and immunecompetent cells have been shown to play a modulatory role in the response to inflammation and injury, and in processes modifying nociception. In the dorsal horn of the spinal cord, wherein the primary processing of nociceptive information occurs, N-methyl-D-aspartate receptors are activated by glutamate released from nocisponsive afferent fibres. Their activation plays a key role in the induction of neuronal sensitization, a process underlying prolonged painful states. In addition, upon peripheral nerve injury, a reduction of inhibitory interneurone tone in the dorsal horn exacerbates sensitized states and further enhance nociception. As concerns the transfer of nociceptive information to the brain, several pathways other than the classical spinothalamic tract are of importance: for example, the postsynaptic dorsal column pathway. In discussing the roles of supraspinal structures in pain sensation, differences between its 'discriminative-sensory' and 'affective-cognitive' dimensions should be emphasized. The purpose of the present article is to provide a global account of mechanisms involved in the induction of pain. Particular attention is focused on cellular aspects and on the consequences of peripheral nerve injury. In the first part of the review, neuronal pathways for the transmission of nociceptive information from peripheral nerve terminals to the dorsal horn, and therefrom to higher centres, are outlined. This neuronal framework is then exploited for a consideration of peripheral, spinal and supraspinal mechanisms involved in the induction of pain by stimulation of peripheral nociceptors, by peripheral nerve injury and by damage to the CNS itself. Finally, a hypothesis is forwarded that neurotrophins may play an important role in central, adaptive mechanisms modulating nociception. An improved understanding of the origins of pain should facilitate the development of novel strategies for its more effective treatment.

Animals↗

PubMed2004

In vivo evidence for apoptosis, but not inflammation in the hindlimb muscle of neuropathic rats.

Loose ligation of the rat sciatic nerve (chronic constriction injury (CCI) model) provokes signs and symptoms like those observed in complex regional pain syndrome (CRPS) patients. Neurogenic inflammation is a purported cause of neuropathic pain despite inconsistent evidence to support this hypothesis. To clarify this issue, we examined effects of CCI on microcirculation, inflammatory cell-cell interaction and cell integrity in muscle tissue using intravital fluorescence microscopic, molecular and immunohistochemical techniques. CCI-rats, but not sham-operated animals developed symptoms of neuropathic pain and oedema on the ipsilateral hindpaw. Despite signs of neuropathic pain, high resolution in vivo multifluorescence microscopy revealed physiological values for functional capillary density, leukocyte-endothelial cell interaction and microvascular permeability in muscle tissue of CCI-animals, similarly as found in controls, indicating absence of perfusion failure and inflammatory cell reaction. However, CCI-animals represented with marked apoptosis of bisbenzimide-stained muscle tissue cells, as given by in vivo fluorescence microscopic assessment of cell death-associated condensation, fragmentation and/or crescent-shaped formation of their nuclear chromatin. Apoptosis was further confirmed by increased caspase 3 protein levels and positive terminal deoxyuridine nick end labeling histochemistry. The present study demonstrates that sciatic nerve ligation-induced neuropathy causes cell apoptosis without concomitant inflammation-associated microcirculatory dysfunction in muscle tissue. Beside the well-known pattern of neuropathic pain, the CCI-model has now additionally been shown to reflect the response of muscle tissue to impaired innervation, i.e. prompting muscle cells to undergo non-inflammatory apoptotic cell death. This finding deserves further investigation in that apoptosis may contribute to neuropathic pain conditions like CRPS.

Animals↗

PubMed1999

Fatty acid interaction with mitochondrial uncoupling proteins.

The phenomena of fatty acid interaction with mitochondrial integral membrane proteins, namely uncoupling proteins (UCPs), are reviewed to emphasize the fatty acid cycling mechanism that has been suggested to explain the UCP function. Fatty acid-induced uncoupling is suggested to serve in bioenergetic systems, to set the optimum efficiency, and to tune the degree of coupling of oxidative phosphorylation. Fatty acid interaction with the "classic" uncoupling protein (UCP1) from mitochondria of thermogenic brown adipose tissue (BAT) is well known. UCP1 is considered to mediate purine nucleotide-sensitive uniport of monovalent unipolar anions, including anionic fatty acids. The return of protonated fatty acid leads to H+ uniport and uncoupling. Experiments supporting this mechanism are also reviewed for plant uncoupling mitochondrial protein (PUMP) and ADP/ATP carrier. The fatty acid cycling mechanism is predicted, as well for the recently discovered uncoupling proteins, UCP2 and UCP3.

Adipose Tissue, Brown↗

PubMedDate not supplied

The hepatic interaction of aliphatic alcohols with halogenated hydrocarbons.

As has been noted, advancement in understanding of chemical interactions requires an integrated approach. Given the large number of binary mixtures of aliphatic alcohols and halogenated hydrocarbons that can be formulated, and because limitations of time and resources make it impossible to test them all, careful thought should be given to selection of pairs for laboratory experimentation. For any given pair of chemicals, the type of interaction (addition, synergism, antagonism, potentiation) should be determined and described by appropriate experimental designs and statistical methodology. This has been done for various alcohol-halocarbon mixtures. Work to expand our understanding of the mechanism(s) underlying the interaction of aliphatic alcohols and halogenated hydrocarbons would be particularly useful, as an improved mechanistic understanding would improve our ability to extrapolate across dose levels (from high laboratory exposure concentrations to typical human environmental exposure concentrations) and across species (from laboratory animals to humans).

Alcohols↗

PubMed2000

Depressive symptoms and lack of social integration in relation to prognosis of CHD in middle-aged women. The Stockholm Female Coronary Risk Study.

AIMS: Several studies have reported that women with coronary heart disease have a poorer prognosis than men. Psychosocial factors, including social isolation and depressive symptoms have been suggested as a possible cause. However, little is known about these factors and their independent predictive value in women. Therefore, we investigated the prognostic impact of depression, lack of social integration and their interaction in the Stockholm Female Coronary Risk Study. METHODS AND RESULTS: Two hundred and ninety-two women patients aged 30 to 65 years and admitted for an acute coronary event between 1991 and 1994, were followed for 5 years from baseline assessments, which were performed between 3 and 6 months after admission. Lack of social integration and depressive symptoms, assessed at baseline by standardized questionnaires, were associated with recurrent events, including cardiovascular mortality, acute myocardial infarction and revascularization procedures (percutaneous transluminal coronary angioplasty and coronary artery bypass grafting). Adjusting for age, diagnosis at index event, symptoms of heart failure, diabetes mellitus, high density lipoprotein (HDL) cholesterol, history of hypertension, systolic blood pressure, smoking, sedentary lifestyle, body mass index, and severity of angina pectoris symptoms, the hazard ratio associated with low (lowest quartile) as compared to high social integration (upper quartile) was 2.3 (95% CI 1.2-4.5) and the hazard ratio associated with two or more (upper three quartiles) as compared to one or no depressive symptoms was 1.9 (95% CI 1.02-3.6). CONCLUSIONS: The presence of two or more depressive symptoms and lack of social integration independently predicted recurrent cardiac events in women with coronary heart disease. Women who were free of both these risk factors, had the best prognosis.

Acute Disease↗

PubMed2007

Prediction-based fingerprints of protein-protein interactions.

The recognition of protein interaction sites is an important intermediate step toward identification of functionally relevant residues and understanding protein function, facilitating experimental efforts in that regard. Toward that goal, the authors propose a novel representation for the recognition of protein-protein interaction sites that integrates enhanced relative solvent accessibility (RSA) predictions with high resolution structural data. An observation that RSA predictions are biased toward the level of surface exposure consistent with protein complexes led the authors to investigate the difference between the predicted and actual (i.e., observed in an unbound structure) RSA of an amino acid residue as a fingerprint of interaction sites. The authors demonstrate that RSA prediction-based fingerprints of protein interactions significantly improve the discrimination between interacting and noninteracting sites, compared with evolutionary conservation, physicochemical characteristics, structure-derived and other features considered before. On the basis of these observations, the authors developed a new method for the prediction of protein-protein interaction sites, using machine learning approaches to combine the most informative features into the final predictor. For training and validation, the authors used several large sets of protein complexes and derived from them nonredundant representative chains, with interaction sites mapped from multiple complexes. Alternative machine learning techniques are used, including Support Vector Machines and Neural Networks, so as to evaluate the relative effects of the choice of a representation and a specific learning algorithm. The effects of induced fit and uncertainty of the negative (noninteracting) class assignment are also evaluated. Several representative methods from the literature are reimplemented to enable direct comparison of the results. Using rigorous validation protocols, the authors estimated that the new method yields the overall classification accuracy of about 74% and Matthews correlation coefficients of 0.42, as opposed to up to 70% classification accuracy and up to 0.3 Matthews correlation coefficient for methods that do not utilize RSA prediction-based fingerprints. The new method is available at http://sppider.cchmc.org.

Artificial Intelligence↗

PubMed2006

Intramembrane receptor-receptor interactions: a novel principle in molecular medicine.

In 1980/81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and long-lived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A/D2, A2A/D3 and A2A/mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A/D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.

Animals↗