Functional asymmetry estimated by measurements of otolith in fish.

It is widely accepted that the incidence of space adaptation syndrome (SAS) is due to a mismatch of sensory information from various receptors to the central nervous system. We investigated the functional asymmetry of vestibular organ, which may caused sensory conflict in space, by measuring the weight difference of otolith between left and right side in goldfish and carp. In the goldfish utricular otolith, the maximum difference was 0.8 mg and the mean difference was 0.091 mg. The percentage of weight difference to the heavier otolith was calculated. The maximum difference was 20.57% and the mean was 3.035%. A difference exceeding 10% was found in only 2 goldfish. In the carp utricular otolith, the maximum percentage difference of weight was 24.8% and the mean was 3.491%. A difference exceeding 10% was found in only 3 carp. The maximum difference of saccular otolith was 11.8% with the mean of 6.92%, and that of lagenar otolith was 32% with the mean of 5.6% in goldfish. The close relationship of utricular otolith weight between both sides suggested that the otolith asymmetry might not be the main factor inducing SAS at least in goldfish and carp.     

Functional asymmetry in kinesin and dynein dimers

Active transport along the microtubule lattice is a complex process that involves both the Kinesin and Dynein superfamily of motors. Transportation requires sophisticated regulation much of which occurs through the motor's tail domain. However, a significant portion of this regulation also occurs through structural changes that arise in the motor and the microtubule upon binding. The most obvious structural change being the manifestation of asymmetry. To a first approximation in solution, kinesin dimers exhibit twofold symmetry, and microtubules exhibit helical symmetry. The higher symmetries of both the kinesin dimers and microtubule lattice are lost on formation of the kinesin–microtubule complex. Loss of symmetry has functional consequences such as an asymmetric hand‐over‐hand mechanism in plus‐end‐directed kinesins, asymmetric microtubule binding in the Kinesin‐14 family, spatially biased stepping in dynein and cooperative binding of additional motors to the microtubule. This review focusses on how the consequences of asymmetry affect regulation of motor heads within a dimer, dimers within an ensemble of motors, and suggests how these asymmetries may affect regulation of active transport within the cell.     

Functional asymmetry in carotid sinus cardiac reflexes in humans

The reflex cardiac response to activation (CBA) and inactivation (CBI) of the left and right carotid baroreceptors was studied in 30 healthy subjects, aged between 24 and 38 years. The CBA was evoked by applying negative pressure (from -20 to -60 mmHg) for 10 s to the left and right carotid sinus regions separately or both together, using two small neck capsules. The CBI was produced by applying left and right positive neck pressure (from 20 to 60 mmHg) for 10 s. The blood flow velocity was measured non-invasively with a Doppler scanner placed in the suprasternal notch. Blood flow acceleration was calculated and used as an indication of left cardiac contractility. Heart rate was measured continuously. Differences were found between right and left carotid sinus responses to CBA and CBI. The maximal response of the R-R interval was significantly greater during right CBA than during left CBA (the average gain: R-R.mmHg-1 2.69 ms.mmHg-1 and 1.75 ms.mmHg-1, respectively). Also, the reflex CBI response was significantly greater for the right (3.16 ms.mmHg-1) than for the left (2.22 ms.mmHg-1). The reflex decrease/increase in blood-flow acceleration in response to CBA/CBI was significantly greater during left than during right-sided activation/inactivation. It is suggested that the functional asymmetry was related to differences in right/left-sided cardiac innervation as well as to central ipsilateral projection of the carotid baroreceptor afferents to the nuclei tractus solitarii.     

Functional asymmetry of the amine transporter from chromaffin granules

The studies presented in this communication describe the existence of a pH-dependent kinetic barrier in amine translocation in membrane vesicles isolated from chromaffin granules from bovine adrenal medulla. This barrier prevents efflux of amines previously accumulated in the membrane vesicles. In these preparations, once the amine is accumulated, there is no further need for ATP. This would suggest a low permeability of the membrane, both to ions and to the amine. In addition, we show that under conditions which thermodynamically favour efflux this is kinetically blocked. This block is due to a rapid protonation of the transporter in the interior of the vesicle. Net efflux can be induced by agents that bring upon an alkalinization of the internal pH such as ammonium salts or nigericin. On the other hand, the rate of exchange with extravesicular substrate is almost identical at the various pH values tested. The physiological implications of this mechanism are discussed.     

Functional asymmetry of transmembrane segments in nicotinic acetylcholine receptors

Nicotinic acetylcholine receptors are heteropentameric ion channels that open upon activation to a single conducting state. The second transmembrane segments of each subunit were identified as channel-forming elements, but their respective contribution in the gating process remains unclear. Moreover, the detailed impact of variations of the membrane potential, such as occurring during an action potential, on the transmembrane domains, is unknown. Residues at the 12′ position, close to the center of each second transmembrane segment, play a key role in channel gating. We examined their functional symmetry by substituting a lysine to that position of each subunit and measuring the electrical activity of single channels. For 12′ lysines in the α, γ and δ subunits rapid transitions between an intermediate and large conductance appeared, which are interpreted as single lysine protonation events. From the kinetics of these transitions we calculated the pK _a values of respective lysines and showed that they vary differently with membrane hyperpolarization. Respective mutations in β or ε subunits gave receptors with openings of either intermediate or large conductance, suggesting extreme pK _a values in two open state conformations. The results demonstrate that these parts of the highly homologous transmembrane domains, as probed by the 12′ lysines, sense unequal microenvironments and are differently affected by physiologically relevant voltage changes. Moreover, observation of various gating events for mutants of α subunits suggests that the open channel pore exists in multiple conformations, which in turn supports the notion of functional asymmetry of the channel.     

Functional regional asymmetry of the EEG intrahemispheric coherence in dogs during conditioning

Individual features of the regional interhemispheric relations in the brain were studied in dogs during alimentary conditioning. The electrical activity was recorded from symmetrical anterior (frontal and motor cortices) and posterior (visual and auditory cortices) areas of the neocortex. Comparison between the averaged left and right intrahemispheric EEG coherences revealed a dynamic character of interhemispheric relations dependent on the stage of conditioning. Individual features were shown. In a dog with strong type of the nervous system, in the anterior brain regions, the EEG coherence was higher in the left hemisphere than in the right one, whereas, on the contrary, in the posterior regions, the values were higher in the right than in the left hemisphere. In dogs with weak type of the nervous system, there was an inverse relationship. Thus, the spatial organization of the cortical electrical activity in the associative and projection brain areas was different.     

Functional asymmetry of the neocortex electrical activity during food conditioning in dogs

Four dogs were trained to perform a conditioned alimentary response to a sound stimulus. The EEG was recorded from six pairs of chronically implanted neocortical electrodes. The EEG spectra and coherence functions between the neighboring derivations of each of the hemispheres were analyzed in the theta, alpha, beta 1 and beta 2 frequency ranges. At the first stages of conditioning, the percent of cases increased when the highest mean values of EEG frequency were localized in the left hemisphere. Later on the percent of cases, when the mean coherence values in the left hemisphere were higher than in the right hemisphere, also increased. At the stage of conditioned response stabilization, this asymmetry either disappeared or the right hemisphere became more active than the left one. The spatial localization of the maximal values of the EEG frequency was different for different frequency ranges. The highest values in the beta 1 range were more frequently registered in the posterior cortical regions and in the beta 2 range they were revealed, predominantly, in the anterior areas. The maximal values of coherence dominated in the anterior regions and their spatial distribution was similar for different frequencies. Thus, the initial stages of conditioning are accompanied by activation of the left hemisphere.     

Functional asymmetry of the regions juxtaposed to the membrane-binding sequence of polyomavirus middle T antigen.

The functional importance of the two clusters of positively charged amino acids which flank the hydrophobic membrane-anchoring sequence of polyomavirus middle T (mT) protein has been investigated by using site-directed mutagenesis. A clear asymmetry was apparent. No effect on transformation was seen following multiple alterations or complete removal of the cluster at the carboxyl end of the protein. In contrast, a single substitution replacing the first arginine amino terminal to the hydrophobic stretch with glutamic acid, but not with lysine, histidine, or methionine, produced a partially transformation-defective mutant with a novel phenotype. This mutant failed to confer anchorage-independent growth on F111 established rat embryo fibroblasts but induced foci with altered morphology compared with wild-type mT. Biochemical studies on this mutant revealed that F111 clones expressing levels of mutant mT equivalent to those of wild-type controls showed a 65% reduction in pp60c-src activation and an 87% reduction in mT-associated phosphatidylinositol 3-kinase activity. However, F111 clones expressing seven times more mutant mT than did wild-type controls showed equal or greater levels of kinase activities yet remained incompletely transformed. Possible mechanisms involving this transformation-sensitive region of mT are discussed.     

Functional and pathological significance of phospholipid asymmetry in erythrocyte membranes

The normal asymmetric distribution of phospholipids in the plasma membrane is perturbed in erythrocytes from patients with chronic myelogenous leukemia. Since experimentally-produced lipid-symmetric erythrocytes are more interactive with cells of the reticuloendothelial system than are their lipid-asymmetric counterparts, the biological recognition of chronic myelogenous leukemia erythrocytes by the reticuloendothelial system was examined. With one exception, all erythrocyte samples from patients with chronic/benign chronic myelogenous leukemia were more adherent to endothelial cells and more readily phagocytosed by macrophagesin vitro than were normal erythrocytes. Thus, these naturally occurring pathological erythrocytes display the same dysfunctional intercellular interactions as the laboratory models.     

Functional asymmetry of the two nucleotide binding domains in the ABC transporter Ste6

The yeast a-factor transporter Ste6 is a member of the ABC transporter family and is closely related to human MDR1. We constructed a set of 26 Ste6 mutants using a random mutagenesis approach. Cell fractionation experiments demonstrated that most of the mutants, with the notable exception of those with alterations in TM1, are transported to the plasma membrane, the presumptive site of action of Ste6. Trafficking, therefore, does not seem to be affected in most of the mutants. To identify regions in Ste6 that interact with the ABC transporter "signature motif" (LSGGQ) we screened for intragenic revertants of the LSGGQ mutant M68 (S507N). Suppressor mutations were identified in TM12 and upstream of TM6. Surprisingly, these mutations also suppressed the Walker A mutation G397D, which should be defective in ATP-binding and hydrolysis at NBD1. Photoaffinity labeling experiments with 8-azido-[alpha-32P]ATP showed that ATP binding at NBD2 is reduced by the suppressor mutation in TM12. The experiments further suggest that the two NBDs of Ste6 are not equivalent and affect each other's ability to bind and hydrolyze ATP.     

Functional directional asymmetry in fallow deer (Dama dama) antlers

The right antlers of fallow deer are significantly more developed than the left antlers with respect to the lengths of the beam, trez tine and palm, as well as antler weight and number of points. The cross-section at the base is also more elliptical in the right antler. The size difference is correlated with the more intense use of right antlers in fighting, and with the greater breadth of the areas of insertion of the neck muscles in the skull's nuchal region.