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PubMed1998

Purification and functional characterization of a low-molecular-mass Ca2+,Mg2+- and Ca2+-ATPase modulator protein from rat brain cytosol.

A low-molecular-mass modulator protein having a molecular mass of about 12 kDa has been purified from rat brain cytosol following gel filtration and FPLC/Mono Q anion-exchange chromatographic separation. A number of protein fractions were obtained from an FPLC column when eluted with a 0.1 M NaCl hold gradient. One fraction (peak no. 5) was found to stimulate Ca2+,Mg2+-ATPase but inhibit Ca2+-ATPase isolated from goat spermatozoa. The S50 (concentration producing 50% stimulation) and I50 were found to be in the nanomolar range. The modulator seems to bind to Ca2+, Mg2+- or Ca2+-ATPase at a site distal from the ATP binding site. The binding to both the ATPases is reversible and non-competitive in nature. The inhibitory activity is found to depend significantly on -SH or -NH2 group(s) of the modulator, whereas no appreciable dependency of the stimulatory effect was apparent. The study indicates that the modulator is not a glycoprotein. CD analysis suggests that the protein exists as an unordered secondary structure. An immuno-cross-reactivity study with specific antibody and inhibition by thapsigargin suggests that the Ca2+,Mg2+- and Ca2+-ATPases from goat testes microsomal membranes are two isoforms of the sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase (SERCA) family. The modulator does not contain any Trp molecules, as evident from Trp fluorescence analysis. Amino acid analysis shows that glycine, serine, derivatives of tyrosine and phenylalanine are the predominant amino acids. The data suggest that the modulator is a negatively charged protein and is a good tool for distinguishing the regulation of Ca2+,Mg2+- and Ca2+-ATPase activities.

Animals↗
PubMed2004

Allosteric modulators of metabotropic glutamate receptors: lessons learnt from mGlu1, mGlu2 and mGlu5 potentiators and antagonists.

Although relatively few G-protein-coupled receptors are Class C, in recent years, this small family of receptors has become a focal point for the discovery of new and exciting allosteric modulators. The mGlu (metabotropic glutamate) receptors are illustrative in the discovery of both positive and/or negative allosteric modulators with unique pharmacological properties. For instance, allosteric modulators of the mGlu2 receptor act as potentiators of glutamate responses in clonal expression systems and in native tissue assays. These potentiators act to increase the affinity of orthosteric agonists for the mGlu2 receptor and shift potency curves for the agonist to the left. In electrophysiological experiments, the potentiators show a unique activation-state-dependent presynaptic inhibition of glutamate release and significantly enhance the receptor-mediated increase in G-protein binding, as seen with autoradiography. Similarly, potentiators of mGlu5 have been described, as well as allosteric antagonists or inverse agonists of mGlu1 and mGlu5. Binding and activity of the modulators have recently indicated that positive and negative allosteric sites can be, but are not necessarily, overlapping. Compared with orthosteric ligands, these modulators display a unique degree of subtype selectivity within the highly conserved mGlu family of receptors and can have very distinct pharmacological properties, such as neuronal frequency-dependent activity. This short review describes some of the unique features of these mGlu1, mGlu2 and mGlu5 allosteric modulators.

Allosteric Regulation↗
PubMed1986

Modulation detection by patients with eighth-nerve tumors.

Detection thresholds for sinusoidally amplitude-modulated broad-band noise were measured as a function of modulation frequency for 4 normally hearing listeners and for 6 patients suffering eighth-nerve tumors. Measurements were obtained using a method-of-adjustment (MOA) procedure. On average, the threshold values revealed that more modulation was needed across all modulation frequencies for the patients' affected ears relative to either the normally hearing listeners or the patients' better ears. The cutoff frequency derived from the average modulation-threshhold function (MTF) for the affected ears was about half the normal value. For a simple lowpass-filter model of the process, the latter result suggested a doubling of the auditory time constant in the affected ears. These patients, on average, exhibited the characteristic high-frequency audiometric hearing loss most often associated with eighth-nerve tumors. Their MTFs closely resembled MTFs described previously for high-frequency audiometric hearing loss. The results of statistical analyses suggested that high frequency audiometric hearing loss, irrespective of other influences, is the most parsimonious explanation for the increased modulation thresholds measured for the eighth-nerve tumor patients.

Adult↗
PubMed1992

Modulation detection in subjects with relatively flat hearing losses.

Modulation detection thresholds were measured as a function of modulation frequency in 5 normal-hearing subjects and in 8 subjects with relatively flat, slight-to-moderate hearing losses. The carrier was a broadband noise that was sinusoidally amplitude modulated (SAM) in one of two observation intervals. The spectrum level of the carrier ranged from -10 to 50 dB SPL, and, for a given carrier level, modulation frequency varied from 2 to 1024 Hz. The temporal modulation transfer functions (TMTFs) were fitted very well with a simple equation describing a low-pass filter function. The TMTFs from the normal-hearing subjects were relatively independent of carrier level, although the derived time constant tended to increase slightly with decreases in carrier level, from an average value of 2.5 msec at 30 dB SPL to 6.0 msec at -10 dB SPL. In addition, sensitivity to amplitude modulation (AM) decreased by about 4 dB as the pressure spectrum level of the carrier was decreased from 0 to -10 dB SPL. The TMTFs from 7 of the 8 hearing-impaired subjects were similar to those from the normal-hearing subjects when the carriers were presented at equal SPLs, except that the derived time constants were slightly larger in the subjects with hearing impairment. When comparisons were made at comparable sensation levels (SLs), however, the TMTFs from the two groups of subjects were quantitatively similar, with the exception that at the lowest SL (20 dB), hearing-impaired subjects typically were more sensitive to AM than normal-hearing subjects, and the derived time constants from their TMTFs were somewhat smaller. These results, taken together with previously published results, suggest that a broad listening bandwidth is important for normal performance on a temporal resolution task. That the time constant from one of the hearing-impaired subjects was significantly longer than normal, regardless of whether the comparisons were made at equal SPL or equal SL, indicates that other factors can also be important.

Adult↗
PubMedDate not supplied

Identification of two distinct intracellular sites that contribute to the modulation of multidrug resistance in P388/ADR cells expressing P-glycoprotein.

Although the ability of chemosensitizers to modulate P-glycoprotein (PGP)-based multidrug resistance (MDR) has been extensively studied, relatively little is known about the cellular pharmacology of the PGP inhibitors themselves in MDR cells. The studies described here have correlated the in vitro accumulation and retention properties of verapamil (VRP) in murine P388 (sensitive) and P388/ADR (MDR) cells with doxorubicin (DOX) uptake and cytotoxicity modulation characteristics in order to better understand VRP-tumor cell interactions that give rise to MDR modulation. VRP is rapidly taken up by DOX-sensitive and -resistant P388 cells where greater than 50% maximal VRP uptake occurs within 10 min of initial exposure at 37 degrees C. Whereas chemosensitization and DOX uptake in P388/ADR cells increase with increasing VRP concentration until a plateau is achieved at approximately 5 microM VRP, cellular modulator levels increase proportionally with increasing VPR concentrations beyond 20 microM. Subsequent to removal of noncell-associated modulator, VRP levels in both sensitive and resistant cells rapidly fall below 10% of those obtained at uptake equilibrium. However, a residual amount of VRP remains associated with the cells for extended time periods after the cells are washed. Pulse exposures of P388/ADR cells to high concentrations of VRP (50-100 microM) are capable of providing extended cell-associated VRP levels comparable to those obtained with continuous exposure at biologically active VRP concentrations (1-3 microM) and this leads to chemosensitization. These results are consistent with the existence of high- and low-affinity intracellular VRP pools in P388 MDR cells, both of which can contribute to the reversal of drug resistance. It is suggested that these properties should be taken into consideration during the design and evaluation of preclinical in vivo MDR models where pulsed exposure to high concentrations of resistance modulators often occurs. Special attention must be given to whether such high concentration pulses are desirable and/or achievable in relevant clinical settings.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Common slow modulation of respiration, arterial blood pressure and cortical activity during sleep onset while napping.

Using healthy subjects, concomitant 30- to 60-s modulations of respiration, arterial blood pressure and EEG activity were found in 21 experiments about napping. Although mean arterial pressure (MAP) modulations above and below 1/30 Hz increased, in respiratory amplitude (RA) only the lower frequency components augmented significantly. This slow modulation of RA was found to be asymmetrical in time, the duration of RA decreasing parts in the modulation waves being 42% longer than the duration of RA increasing parts. The concomitance of the slow modulations in the different organ systems is accounted for by the influence of the common brainstem system (CBS), which regulates and integrates respiratory, cardiovascular and somatomotor systems and the adjustment of central nervous activity (vigilance). The described common, slow modulations outline the importance of dampening influences during sleep onset. They may provide an important tool for the investigation of the regulatory systems during sleep onset, as well as for investigations about sleep apnoea syndrome and Cheyne-Stokes breathing.

Adult↗
PubMed2000

Two new microscopical variants of thermomechanical modulation: scanning thermal expansion microscopy and dynamic localized thermomechanical analysis

We describe two ways in which thermomechanical modulation may be used in conjunction with scanning thermal microscopy, in order to distinguish between different components of an inhomogeneous sample. The sample is subjected to a modulated mechanical stress, and the heating is supplied locally by the probe itself. Scanning thermal expansion microscopy is an imaging mode, in which an imposed localized temperature modulation is used to generate thermal expansion, which in turn produces mechanical strain and gives thermal expansion contrast images. We present results using two types of active thermal probe. For polymer/resin samples, the depth of material contributing to the measured thermal expansion is typically a few micrometres. Under certain conditions we observe a reversal in contrast as the frequency of the temperature modulation is increased. In dynamic localized thermomechanical analysis, the modulated stress is applied directly, and accompanied by a localized temperature change, as used in other forms of localized thermal analysis. The resulting modulated lateral force signals are obtained. The glass transition of polystyrene is detected, and shows a significant variation with frequency. The amplitude or phase signal may be used to obtain image contrast for inhomogeneous samples.

Journal Article↗
PubMed2002

Sleep- and circadian-dependent modulation of REM density.

Rapid eye movement (REM) density, a measure of the frequency of rapid eye movements during REM sleep, is known to increase over the course of the sleep episode. However, the circadian modulation of REM density has not been thoroughly evaluated. Data from a forced desynchrony protocol, in which 20 consecutive sleep opportunities were systematically scheduled over the entire circadian cycle, were analysed. The REM density was evaluated from polysomnographically recorded REM sleep episodes, and analyzed as a function of time in the sleep opportunity and as a function of phase in the circadian cycle. The REM density showed a robust increase over the course of the sleep episode. This sleep-dependent increase was observed regardless of circadian phase, because data analyzed from different thirds of the circadian cycle exhibited a similar pattern. The REM density did not show a significant circadian-dependent modulation for data from the entire sleep opportunity. However, analysis of circadian modulation from separate thirds of the sleep opportunity revealed a significant circadian modulation in the last third of the sleep episode. Maximum REM densities were observed when the last third of the sleep episode coincided with the wake-maintenance zone, i.e.;8-10 h before the crest of the circadian rhythm of REM sleep propensity. These results confirm the dominant sleep-dependent modulation of REM density, and indicate that the density of REMs is greatest when sleep pressure is low, such as in the latter part of the sleep episode, at which time the circadian modulation of REM density is also appreciable.

Adult↗
PubMed2001

Designing a community-based fourth-year obstetrics and gynaecology module: an example of innovative curriculum development.

INTRODUCTION: This paper describes the design and evaluation of the community-based obstetrics and gynaecology module at St Bartholomew's and the Royal London School of Medicine and Dentistry. This module sets out to comply with the General Medical Council's recommendations of encouraging students to consider the community perspective, and places less emphasis on a disease-orientated approach. OBJECTIVES: The development of the module, issues of improving student acceptance of the course, staff development and the benefits of community teaching in obstetrics and gynaecology are discussed. MODULE ORGANIZATION: The 2-week module precedes the 8-week hospital obstetrics and gynaecology firms that occur in the fourth undergraduate year. The course is organized into three components: general practice, departmental teaching, and self-directed learning. Students are allocated to general practices for their clinical teaching, for eight sessions. Seven departmental sessions are run by the Academic Department of General Practice and Primary Care. These include a review of the students' self-directed learning. EVALUATION AND CONCLUSION: Evaluation data are reported for the three components of the course. Overall the majority of students rated the module as useful, GP attachments being most favourably received. The majority of students have grasped the basic obstetric and gynaecological history and examination skills and found this useful before starting their hospital firms. Aspects of a specialist subject, such as, obstetrics and gynaecology, can be taught successfully in the community and GP tutors are, as yet, an untapped source of excellent obstetric and gynaecology teaching.

Community Medicine↗
PubMed2002

Co-operative binding of triplicate carbohydrate-binding modules from a thermophilic xylanase.

Family 6 carbohydrate-binding modules were amplified by polymerase chain reaction (PCR) from Clostridium stercorarium strain NCIB11754 genomic DNA as a triplet. Individually, these modules bound to xylooligosaccharides and cellooligosaccharides with affinities varying from approximately 3 x 10(3) M(-1) to approximately 1 x 10(5) M(-1). Tandem and triplet combinations of these modules bound co-operatively to soluble xylan and insoluble cellulose to give approximately 20- to approximately 40-fold increases in affinity relative to the individual modules. This co-operativity was an avidity effect resulting from the modules within the tandems and triplet interacting simultaneously with proximal binding sites on the polysaccharides. This occurred by both intrachain and interchain interactions. The duplication or triplication of modules appears to be linked to the growth temperature of the organism; co-operativity in these multiplets may compensate for the loss of affinity at higher temperatures.

Base Sequence↗
PubMed1996

CD5+B cells: differential capping and modulation of IgM and CD5.

CD5 is associated with the B-cell antigen receptor (BcR) complex. As an approach to understanding its role in B-cell function, the authors investigated the capping and modulation of CD5 and surface IgM (sIgM). Tonsillar B cells were treated with anti-IgM or anti-CD5 antibodies, capping examined after 1 h (by fluorescence microscopy) and modulation after 24 h (by flow cytometry). CD5 co-capped and co-modulated with sIgM. Of various drugs tested, only the protein tyrosine kinase inhibitor (genistein) had any effect on capping and co-capping. Capping of sIgM (and co-capping of CD5) but not capping of CD5 (or co-capping of sIgM) was inhibited by genistein. None of the other drugs affecting PKC or cytoskeletal structures (colchicine and cytochalasin D) had any effect. However, the PKC inhibitors, staurosporine and H-7, inhibited the modulation of sIgM by anti-IgM but not CD5 by anti-CD5. In contrast, PKC activators, PMA and mezerein, inhibited modulation of CD5 by anti-CD5 but not sIgM by anti-IgM. This suggests that direct ligation of CD5 utilizes different signalling pathways compared with sIgM. It seems likely that in CD5+ cells, interaction of CD5 with its ligand CD72 modulates signals transmitted through the BcR.

Antibodies, Monoclonal↗
PubMed1999

Localized scotomata detected with temporal modulation perimetry in central serous chorioretinopathy.

AIM: Flicker deficits have been reported in various maculopathies, including age-related macular degeneration. We test whether flicker losses exist in patients with central serous chorioretinopathy (CSC) and whether the size and flicker frequency of the target is important in detecting such losses. METHODS: We examined four CSC patients with temporal modulation (flicker perception) perimetry using the Medmont auto-flicker module (Medmont Pty Ltd, Melbourne, Vic. Australia), as well as static perimetry and colour vision. One case was examined using sophisticated laboratory equipment to precisely measure their temporal contrast sensitivity function (temporal CSF or de Lange curve) using larger targets to consider the effect of target frequency and size. Two patients were followed longitudinally and tested after resolution of the maculopathy. We compared our patients with an age-matched control group of 11 people. RESULTS: Temporal modulation perimetry detected larger and more localized defects in all cases of active CSC compared with static perimetry. There appeared to be size and frequency tuning to the deficit, with greatest loss being found at 16 Hz with small (0.5 degree) targets. The losses resolved in one case where the retina recovered in 4 weeks, but remained to a lesser degree in another case who suffered a 2 year long fluctuating course before the CSC subsided. CONCLUSIONS: Temporal modulation perimetry detects a loss of flicker sensitivity in patients with CSC. Deeper and more clearly defined scotomata are found with a flickering stimulus compared with a steady state one. The greatest losses of flicker sensitivity are found with 16 Hz modulation and with small targets located directly over the lesion. The duration of the disease may be important for recovery of flicker sensitivity. Temporal modulation perimetry appears to be a valuable tool for the confirmation of functional loss due to CSC.

Adult↗
PubMed2003

Basolateral amygdala modulation of the nucleus accumbens dopamine response to stress: role of the medial prefrontal cortex.

The basolateral amygdala (BLA) is involved in modulating affective responses to stress and, along with the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), receives a stress-responsive dopamine (DA) projection from the ventral tegmental area. The present study was undertaken to characterize the role of BLA DA D1 and D2/D3 receptor subtypes in modulating the NAc and mPFC DA responses to stress. Voltammetry was used to monitor, in freely behaving rats, stress-induced DA release in NAc or mPFC after injection of D1 (SCH 23390) or D2/D3 (raclopride) receptor antagonist into BLA. Intra-BLA SCH 23390 injection potentiated stress-induced NAc DA release but attenuated the mPFC DA stress response; raclopride had no effect on either the NAc or mPFC DA responses to stress. Based on these results, we also examined the possibility that BLA can indirectly modulate the NAc DA stress response via its projection to mPFC. To do so we studied the effects of intra-mPFC co-administration of D1 (SKF 38393) and D2/D3 (quinpirole) receptor agonists on the potentiated NAc DA stress response resulting from intra-BLA SCH 23390 injection. Alone, mPFC D1 and D2/D3 receptor co-activation had no effect on stress-induced NAc DA release, but did prevent the potentiated NAc DA stress response produced by BLA D1 receptor blockade. These findings indicate that BLA DA modulates the NAc and mPFC DA stress responses via activation of the D1 receptor subtype. They also suggest that BLA DA modulates stress-induced NAc DA release indirectly by modulating the mPFC DA response to stress.

Amygdala↗
PubMed2000

Blood bank conditions and RBCs: the progressive loss of metabolic modulation.

BACKGROUND: Human RBC metabolism is modulated by the cell oxygenation state. Among other mechanisms, competition of deoxyhemoglobin and some glycolytic enzymes for the cytoplasmic domain of band 3 is probably involved in modulation. This metabolic modulation is connected to variations in intracellular NADPH and ATP levels as a function of the oxygenation state of the cell, and, consequently, it should have physiologic relevance. The present study investigates the effect of storage on this metabolic modulation and its relationship with the alteration of membrane protein composition. STUDY DESIGN AND METHODS: RBCs stored in CPD-saline-adenine-glucose-mannitol were assayed for glucose uptake and partition between glycolysis and the pentose phosphate pathway at high and low oxygen saturation by nuclear magnetic resonance spectroscopy after 1, 14, 21, 35, and 42 days of storage. Membrane protein composition was determined by SDS-PAGE on Days 1, 14, 35, and 42. Metabolic values and 2,3 DPG concentration were also measured after rejuvenation for 1 hour at 37 degrees C with pyruvate-inosine-phosphate-adenine solution on Day 21. RESULTS: Metabolic differences between RBCs incubated at high and low oxygen saturation decreased during storage, and, on Day 35, the two groups did not have significant differences (p = 0.111). SDS-PAGE showed that membrane protein composition was concurrently modified. The percentage of unmodified band 3 decreased during storage, principally between Days 14 and 35. In rejuvenated RBCs, oxygen-dependent modulation was not restored. CONCLUSIONS: RBCs stored in CPD-saline-adenine-glucose-mannitol do show a progressive loss of oxygen-dependent metabolic modulation, which is not restored after rejuvenation and which seems partly related to modifications in membrane proteins, mainly band 3.

Adenine↗
PubMed1999

[Dosage reduction in computed tomography by anatomy-oriented attenuation-based tube-current modulation: the first clinical results].

PURPOSE: To examine the feasibility of reducing exposition in CT examinations by applying a prototype device for tube current modulation with the image quality remaining unchanged. PATIENTS AND METHODS: The prototype device for tube current modulation was integrated into a Somatom Plus 4 CT scanner (Siemens). The method is based on anatomy-oriented modulation of the tube current. The attenuation of the X-ray beam by the patient's body was determined online, the tube current was adapted to changing anatomy after a delay of 180 degrees. In ten patients undergoing radiotherapy, four identical scans of the shoulder region were carried out with and without tube current modulation. For determining dose reduction, mAs product of both scans were compared. The evaluation of noise artifacts, low contrast detectability and overall image quality was performed by four radiologists in a blinded fashion. RESULTS: Patient doses could be reduced by 38% on an average. Scans with tube current modulation were superior to scans without it as to noise (75%), low contrast detectability (51%), artifacts (69%), and overall image quality (71%). CONCLUSIONS: A significant reduction in exposition during CT can be achieved by anatomy-oriented tube current modulation without image degradation.

Artifacts↗
PubMed2005

Steady dark solitary waves emerging from wave-generated meanflow: the role of modulation equations.

Various classes of steady and unsteady dark solitary waves (DSWs) are known to exist in modulation equations for water waves in finite depth. However, there is a class of steady DSWS of the full water-wave problem which are missed by the classical modulation equations such as the Hasimoto-Ono, Benney-Roskes, and Davey-Stewartson. These steady DSWs, recently discovered by Bridges and Donaldson, are pervasive in finite depth, arise through secondary criticality of Stokes gravity waves, and are synchronized with the Stokes wave. In this paper, the role of DSWs in modulation equations for water waves is reappraised. The intrinsic unsteady nature of existing modulation equations filters out some interesting solutions. On the other hand, the geometry of DSWs in modulation equations is very similar to the full water wave problem and these geometrical properties are developed. A model equation is proposed which illustrates the general nature of the emergence of steady DSWs due to wave-generated mean flow coupled to a periodic wave. Although the existing modulation equations are intrinsically unsteady, it is shown that there are also important shortcomings when one wants to use them for stability analysis of DSWs.

Algorithms↗
PubMed2006

Differential recognition of plant cell walls by microbial xylan-specific carbohydrate-binding modules.

Glycoside hydrolases that degrade plant cell walls have complex molecular architectures in which one or more catalytic modules are appended to noncatalytic carbohydrate-binding modules (CBMs). CBMs promote binding to polysaccharides and potentiate enzymic hydrolysis. Although there are diverse sequence-based families of xylan-binding CBMs, these modules, in general, recognize both decorated and unsubstituted forms of the target polysaccharide, and thus the evolutionary rationale for this diversity is unclear. Using immunohistochemistry to interrogate the specificity of six xylan-binding CBMs for their target polysaccharides in cell walls has revealed considerable differences in the recognition of plant materials between these protein modules. Family 2b and 15 CBMs bind to xylan in secondary cell walls in a range of dicotyledon species, whereas family 4, 6, and 22 CBMs display a more limited capability to bind to secondary cell walls. A family 35 CBM, which displays more restricted ligand specificity against purified xylans than the other five protein modules, reveals a highly distinctive binding pattern to plant material including the recognition of primary cell walls of certain dicotyledons, a feature shared with CBM15. Differences in the specificity of the CBMs toward walls of wheat grain and maize coleoptiles were also evident. The variation in CBM specificity for ligands located in plant cell walls provides a biological rationale for the repertoire of structurally distinct xylan-binding CBMs present in nature, and points to the utility of these modules in probing the molecular architecture of cell walls.

Bacterial Proteins↗
PubMed2001

Allosteric modulation of Ca2+ channels by G proteins, voltage-dependent facilitation, protein kinase C, and Ca(v)beta subunits.

N-type and P/Q-type Ca(2+) channels are inhibited by neurotransmitters acting through G protein-coupled receptors in a membrane-delimited pathway involving Gbetagamma subunits. Inhibition is caused by a shift from an easily activated "willing" (W) state to a more-difficult-to-activate "reluctant" (R) state. This inhibition can be reversed by strong depolarization, resulting in prepulse facilitation, or by protein kinase C (PKC) phosphorylation. Comparison of regulation of N-type Ca(2+) channels containing Cav2.2a alpha(1) subunits and P/Q-type Ca(2+) channels containing Ca(v)2.1 alpha(1) subunits revealed substantial differences. In the absence of G protein modulation, Ca(v)2.1 channels containing Ca(v)beta subunits were tonically in the W state, whereas Ca(v)2.1 channels without beta subunits and Ca(v)2.2a channels with beta subunits were tonically in the R state. Both Ca(v)2.1 and Ca(v)2.2a channels could be shifted back toward the W state by strong depolarization or PKC phosphorylation. Our results show that the R state and its modulation by prepulse facilitation, PKC phosphorylation, and Ca(v)beta subunits are intrinsic properties of the Ca(2+) channel itself in the absence of G protein modulation. A common allosteric model of G protein modulation of Ca(2+)-channel activity incorporating an intrinsic equilibrium between the W and R states of the alpha(1) subunits and modulation of that equilibrium by G proteins, Ca(v)beta subunits, membrane depolarization, and phosphorylation by PKC accommodates our findings. Such regulation will modulate transmission at synapses that use N-type and P/Q-type Ca(2+) channels to initiate neurotransmitter release.

Allosteric Regulation↗