PubMed Health⌕ Search

Biomedical subjects

K McCormack

Publications and source records attributed to K McCormack.

At least 37 records · Page 2Linked to original sources
PubMed1994

A characterization of the activating structural rearrangements in voltage-dependent Shaker K+ channels.

In response to changes in membrane potential, voltage-dependent ion channel proteins undergo conformational rearrangements that lead to channel opening. These rearrangements move a net charge, measured as "gating current", across the membrane. Here we characterize the effects of the pharmacological blocker 4-aminopyridine on both the K+ and gating currents of wild-type and mutant Shaker K+ channels. Our results indicate that the activation of these channels involves two distinct types of structural rearrangement. In addition to independent Hodgkin and Huxley type rearrangements for each of the four subunits, which are responsible for most of the gating charge movement, Shaker channels interconvert between two quaternary conformations during activation. The transition between the two quaternary states moves about 10% of the total gating charge, and it is selectively blocked by 4-aminopyridine.

4-Aminopyridine↗
PubMed1994

The spinal actions of nonsteroidal anti-inflammatory drugs and the dissociation between their anti-inflammatory and analgesic effects.

The traditional classification of nonsteroidal anti-inflammatory drugs (NSAIDs) as exclusively 'peripherally acting' agents is no longer valid. For many of these agents there is a growing body of evidence in favour of an additional central mechanism for their anti-inflammatory and analgesic effects. This view is further supported by the recent discovery that a substantial component of the hyperalgesia and allodynia that characterise postinjury hypersensitivity occurs in the CNS, notably the spinal dorsal horn. An important corollary is that inhibition of central nociceptive processing may represent an important analgesic mode of action for those NSAIDs that are effective in the management of pain after tissue injury. Historically, attempts to group this heterogeneous class of compounds into a single entity are largely derived from the observation that the majority of clinically useful NSAIDs are weak organic acids (pKa 3 to 5), bind extensively to plasma albumin (= 99%), and inhibit (to varying degrees) prostaglandin synthesis. However, the significance of these various unifying features is becoming increasingly obscure. While inhibition of prostaglandin synthesis apparently remains an important analgesic mode of action for NSAIDs both in the periphery and the CNS, other mechanisms should be considered. Some NSAIDs, in addition to their effects on prostaglandin synthesis, also affect the synthesis and activity of other neuroactive substances believed to have key roles in processing nociceptive input within the dorsal horn. It has been argued that these other actions, in conjunction with inhibition of prostaglandin synthesis, may synergistically augment the effects of NSAIDs on spinal nociceptive processing. Despite much effort, it remains a formidable task to assess the significance of these differential mechanisms upon clinical pain states. In the meantime, however, it may be possible, on the basis of in vivo studies, to evaluate the impact of putative spinal analgesic mechanisms that are unrelated to inhibition of prostaglandin synthesis. This approach has recently been extended to include the identification of pharmacokinetic and clinical correlates of these derived in vivo parameters, and in this way attempt to demonstrate clinical relevance.

Analgesics↗
PubMed1993

Substitution of a hydrophobic residue alters the conformational stability of Shaker K+ channels during gating and assembly.

A leucine residue at position 370 (L370) in 29-4 Shaker K+ channels resides within two overlapping sequence motifs conserved among most voltage-gated channels: the S4 segment and a leucine heptad repeat. Here we investigate the effects observed upon substitution of L370 with many other uncharged amino acid residues. We find that smaller or more hydrophilic residues produce greater alterations in both activation and inactivation gating than does substitution with other large hydrophobic residues. In addition, subunits containing less conservative substitutions at position 370 are restricted in their assembly with wild-type subunits and are unlikely to form homomultimeric channel complexes. Consistent with the idea that L370 influences the tertiary structure of these channels, the results indicate that L370 undergoes specific hydrophobic interactions during the conformational transitions of gating; similar interactions may take place during the folding, insertion, or assembly of Shaker K+ channel subunits.

Amino Acid Sequence↗
PubMed1993

Cerebral asymmetry and hypnosis: a signal-detection analysis of divided visual field stimulation.

Brightness discriminations in a divided-field paradigm were examined with a signal-detection procedure in three sessions, the second with hypnosis. Practiced, hypnotically susceptible Ss were subdivided into high- (n = 6) and medium- (n = 5) susceptible groups on the basis of a susceptibility scale monitored throughout the hypnosis session. High-susceptible Ss showed increases in d' in the left visual field (right hemisphere) with hypnosis, whereas medium-susceptible Ss showed bilateral enhancements. Beta remained invariant in both groups across three sessions but was higher in the left visual field. The results provide evidence of altered brain function with hypnosis and an association of focal right hemispheric changes with high susceptibility and, through the invariance of beta, fail to support the attribution of perceptual changes to attitudinal, nonstate factors.

Adult↗
PubMed1992

The size of gating charge in wild-type and mutant Shaker potassium channels.

The high sensitivity of voltage-gated ion channels to changes in membrane potential implies that the process of channel opening is accompanied by large charge movements. Previous estimates of the total charge displacement, q, have been deduced from the voltage dependence of channel activation and have ranged from 4 to 8 elementary charges (e0). A more direct measurement of q in Drosophila melanogaster Shaker 29-4 potassium channels yields a q value of 12.3 e0. A similar q value is obtained from mutated Shaker channels having reduced voltage sensitivity. These results can be explained by a model for channel activation in which the equilibria of voltage-dependent steps are altered in the mutant channels.

Animals↗
PubMed1992

Tandem linkage of Shaker K+ channel subunits does not ensure the stoichiometry of expressed channels.

Shaker K+ channels are multimeric, probably tetrameric proteins. Substitution of a conserved leucine residue to valine (V2) at position 370 in the Drosophila Shaker 29-4 sequence results in large alterations in the voltage dependence of gating in the expressed channels. In order to determine the effects of this mutation in hybrid channels with a fixed stoichiometry of V2 and wild-type (WT) subunits we generated cDNA constructs of two linked-monomeric subunits similar to the tandem constructs previously reported by Isacoff, E. Y., Y. N. Jan, and L. Y. Jan. (1990. Nature (Lond.). 345:530-534). In addition, we constructed a tandem cDNA containing a wild-type subunit and a truncated nonfunctional subunit (Sh102) that suppresses channel expression. We report that the voltage-dependence of the channels produced with WT and V2 subunits varied significantly with the order of the subunits in the construct (WT-V2 or V2-WT), while the WT-Sh102 construct yielded currents that were much larger than expected. These results suggest that the tandem linkage of Shaker subunits does not guarantee the stoichiometry of the expressed channel proteins.

Amino Acid Sequence↗
PubMed1991

A role for hydrophobic residues in the voltage-dependent gating of Shaker K+ channels.

A leucine heptad repeat is well conserved in voltage-dependent ion channels. Herein we examine the role of the repeat region in Shaker K+ channels through substitution of the leucines in the repeat and through coexpression of normal and truncated products. In contrast to leucine-zipper DNA-binding proteins, we find that the subunit assembly of Shaker does not depend on the leucine heptad repeat. Instead, we report that substitutions of the leucines in the repeat produce large effects on the observed voltage dependence of conductance voltage and prepulse inactivation curves. Our results suggest that the leucines mediate interactions that play an important role in the transduction of charge movement into channel opening and closing.

Amino Acid Sequence↗
PubMed1991

Dissociation between the antinociceptive and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs. A survey of their analgesic efficacy.

The authors challenge the general view that the analgesic effect of the nonsteroidal anti-inflammatory drugs (NSAIDs) can be universally attributed to their inhibitory effects on the synthesis of peripherally formed prostaglandins. Analgesic activity by some of these compounds in the reduction of physiological pain elicited by a single noxious stimulus, or the treatment of acute pain which results from sudden trauma to otherwise healthy tissue, is better described as an antinociceptive effect. Single-dose studies in the dental pain model that have been conducted in double-blind conditions and included a placebo control group have been reviewed; those NSAIDs which are significantly superior to the reference compound aspirin 650mg and those which could represent real alternatives to the use of narcotics in certain situations for the management of acute pain have been identified. Azapropazone, diflunisal, naproxen, oxaprozin and tolmetin are all weak inhibitors of prostaglandin synthesis, yet they have been shown to be more effective than aspirin. In a model of joint pain, azapropazone 600mg has been shown to be as effective as pethidine (meperidine) 100mg despite being the weakest inhibitor of prostaglandin synthesis. Whether the antinociceptive effect of azapropazone acts at a peripheral or a central level, or both, is not clear; evidence for the effects of NSAIDs on the central nervous system (CNS) is discussed. Historically, the antinociceptive character of some NSAIDs is apparent in several studies in both animals and humans. More recently, experimental algesimetry models designed to distinguish the antinociceptive effects of NSAIDs include the use in humans of photoplethysmography and computer-supported infrared thermographic imaging.

Administration, Oral↗
PubMed1990

Shaker K+ channel subunits from heteromultimeric channels with novel functional properties.

A large number of related genes (the Sh gene family) encode potassium channel subunits which form voltage-dependent K+ channels by aggregating into homomulitimers. One of these genes, the Shaker gene in Drosophila, generates several products by alternative splicing. These products encode proteins with a constant central region flanked by variable amino and carboxyl domains. Coinjection of two Shaker RNAs with different amino or different carboxyl ends into Xenopus oocytes produces K+ currents that display functional properties distinct from those observed when each RNA is injected separately, indicating the formation of heteromultimeric channels. The analysis of Shaker heteromultimers suggests certain rules regarding the roles of variable amino and carboxyl domains in determining kinetic properties of heteromultimeric channels. Heteromultimers with different amino ends produce currents in which the amino end that produces more inactivation dominates the kinetics. In contrast, heteromultimers with different carboxyl ends recover from inactivation at a rate closer to that observed in homomultimers of the subunit which results in faster recovery. While this and other recent reports demonstrate that closely related Sh family proteins form functional heteromultimers, we show here that two less closely related Sh proteins do not seem to form functional heteromultimeric channels. The data suggest that sites for subunit recognition may be found in sequences within a core region, starting about 130 residues before the first membrane spanning domain of Shaker and ending after the last membrane spanning domain, which are not conserved between Sh Class I and Class III genes.

Animals↗
PubMed1990

The amphiprotic character of azapropazone and its relevance to the gastric mucosa.

Since most non-steroidal anti-inflammatory drugs (NSAIDs) contain only one obvious ionisable group at physiological pH levels then they may be easily identified as having either acidic or basic character. Basic NSAIDs are simply non-acidic NSAIDs capable of accepting a proton within the physiological pH range. Within this range, however, a few NSAIDs contain two obvious ionisable groups, one acidic and the other basic. Such compounds should be described as amphiprotic, and include NSAIDs such as 4- and 5-amino substituted salicylic acids, niflumic acid, amfenac, WY 18251, and azapropazone. The aqueous ionisation equilibrium of such compounds is complex and is described by two macroscopic ionisation constants. Evidence has accumulated during the last decade to support the view that the pharmacokinetic behaviour of NSAIDs contributes not only decisively to their therapeutic effects but also to the type and incidence of their side-effects. A priori, using a physicochemical argument, certain amphiprotic NSAIDs should be better tolerated by the gastric mucosa than the classical acidic compound. Of those NSAIDs commercially available in the United Kingdom azapropazone remains the only one for which amphiprotic behaviour has been described. Following our examination of available data for azapropazone we conclude that the use of amphiprotic compounds represents a logical approach towards solving the problem of NSAID-induced gastric mucosal damage.

Animals↗
PubMed1988

Multiple hairy pacinian neurofibromas (nerve-sheath myxomas).

Pacinian neurofibromas are unusual tumors with components that resemble Vater-Pacini corpuscles and are probably a variant of nerve-sheath myxoma. Lesions composed predominantly of these structures have occurred on or near the buttocks in three previously reported cases; however, all were solitary and congenital. Two of these patients, with lesions that closely resembled mature Vater-Pacini corpuscles, had underlying skeletal anomalies. Our patient had multiple hairy pacinian neurofibromas (nerve-sheath myxomas) on the buttocks that were not associated with radiographic evidence of and underlying skeletal anomaly. Skeletal anomalies may be associated with "sacrococcygeal paciniomas" but probably not with true pacinian neurofibromas.

Buttocks↗
PubMed1987

Classical absorption theory and the development of gastric mucosal damage associated with the non-steroidal anti-inflammatory drugs.

Evidence has accumulated during the last decade to support the view that the pharmacokinetic behaviour of non-steroidal anti-inflammatory drugs (NSAIDs) contributes not only decisively to their therapeutic effects but also to the type and incidence of their side effects. It has been shown that NSAIDs reach particularly high concentrations in those compartments in which they cause effects and side effects. Specifically, the data reviewed herein indicate that the accumulation of NSAID within gastric mucosal cells a priori is a principal factor associated with the intervention of intracellular biochemical events and resultant gastric mucosal damage. To a large extent this behaviour is according to the precepts of classical absorption theory; in this respect the limitations of such theory are examined. Our survey further indicates that the failure of certain NSAIDs to significantly reduce gastric mucosal levels of prostaglandins (PG) in vivo may reflect pharmacokinetic differences between NSAIDs rather than tissue-specific differences in their potency as inhibitors of cyclo-oxygenase.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1983

Prognostic indicators of tumor response to Staphylococcus aureus Cowan strain I plasma perfusion.

Ten tumor-bearing dogs were treated with passage of autologous plasma over fixed Staphylococcus aureus Cowan strain I. Five similar dogs were treated identically except for the exposure to S. aureus. These animals have been assessed to identify positive and negative prognostic variables for response. Nonresponder treated animals had significantly larger chest wall tumor bulk than did the responder and control groups (P less than .01). Responder animals had fewer initial circulating immune complexes than did the nonresponders, though each group had similar reductions in immune complexes with therapy. Nonresponder animals had smaller volumes of plasma processed per kilogram of body weight per procedure than did controls (P = .016), whereas responder and control animals had similar volumes processed per kilogram of body weight per procedure (P = .84). These data suggest that the response observed in our original series was significantly related to the larger amount of plasma treated per procedure and suggest that a factor may be eluted from the S. aureus cartridge that mediates this response.

Adenocarcinoma↗
PubMed1982

Phase I trial of Staphylococcus aureus Cowan I immunoperfusion.

Staphylococcus aureus Cowan I has shown antitumor activity in in vitro and in animal tumor models. It is hypothesized that this antineoplastic effect results from the interaction of protein A on the cell surface of Cowan I strain S. aureus and immunosuppressive circulating immune complexes. Therefore, we treated five patients with ex vivo plasma immuno-perfusion over killed and fixed S. aureus Cowan I. Toxic effects were marked in all patients and appeared to be related to the plasma volume infused and rate of infusion. Toxic reactions occurred in the cardiovascular, respiratory, and hematopoietic systems. No responses even minimal or transient, were observed in this phase I trial. This toxicity may be reduced if the rate of plasma infusion decreases.

Adult↗
PubMed1981

Cyclophosphamide treatment expands the circulating hematopoietic stem cell pool in dogs.

Increased numbers of circulating granulocyte-monocyte precursor cells (CFUc) have been observed in the peripheral blood of man after antineoplastic chemotherapy. We have developed a canine model to study the biologic significance of this phenomenon for hematopoietic reconstitution following hematopoietically lethal exposure to total body irradiation (TBI). After cyclophosphamide administration, a 16-fold expansion of circulating CFUc numbers was observed during the period of rapid leukocyte recovery that occurred after the chemotherapy-induced leukocyte nadir. We had previously noted this association between leukocyte recovery and CFUc expansion in our human studies. After 900 rad TBI hematopoietic reconstitution was attempted with autologous, cryopreserved collections of peripheral blood mononuclear cells obtained either at times of post-cyclophosphamide CFUc expansion (group A, 14 dogs) or without CFUc expansion (group B, 12 dogs). Asd compared to group B collections, group A collections contained 11-fold more CFUc and were 12.5-fold more potent in fostering hematopoietic recovery after TBI. These results suggest that the expansion of CFUc numbers we observed was accompanied by a similar expansion of more primitive hematopoietic stem cell numbers. We conclude that chemotherapy-induced expansion of circulating CFUc numbers appears to be of substantial import in effecting hematopoietic reconstitution--an observation that may be of significance for further studies of autologous hematopoietic reconstitution in man.

Animals↗