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K McCormack

Publications and source records attributed to K McCormack.

At least 19 recordsLinked to original sources
PubMed1999

The effects of Shaker beta-subunits on the human lymphocyte K+ channel Kv1.3.

The activation of T-lymphocytes is dependent upon, and accompanied by, an increase in voltage-gated K+ conductance. Kv1.3, a Shaker family K+ channel protein, appears to play an essential role in the activation of peripheral human T cells. Although Kv1.3-mediated K+ currents increase markedly during the activation process in mice, and to a lesser degree in humans, Kv1.3 mRNA levels in these organisms do not, indicating post-transcriptional regulation. In other tissues Shaker K+ channel proteins physically associate with cytoplasmic beta-subunits (Kvbeta1-3). Recently it has been shown that Kvbeta1 and Kvbeta2 are expressed in mouse T cells and that they are up-regulated during mitogen-stimulated activation. In this study, we show that the human Kvbeta subunits substantially increase K+ current amplitudes when coexpressed with their Kv1.3 counterpart, and that unlike in mouse, protein levels of human Kvbeta2 remain constant upon activation. Differences in Kvbeta2 expression between mice and humans may explain the differential K+ conductance increases which accompany T-cell proliferation in these organisms.

Animals↗
PubMed1999

Comparative analgesic effects of H-wave therapy and transcutaneous electrical nerve stimulation on pain threshold in humans.

OBJECTIVE: To assess the comparative analgesic efficacy of H-wave therapy (HWT) and transcutaneous electrical nerve stimulation (TENS) using a mechanical model of pain threshold measurement. STUDY DESIGN: Forty-eight healthy human volunteers (24 women, 24 men) were recruited and randomly assigned into one of six experimental groups; control, HWT (placebo, 2Hz, or 60Hz), or TENS (placebo or 110Hz). For each subject, mechanical pain threshold (MPT) measurements were recorded at three standardized recording points marked on the dorsal web space of the dominant hand. Two MPT measurements were recorded at each point at the following time intervals: before treatment was initiated (baseline), after each of three consecutive 10-minute periods of stimulation (HWT or TENS), and at four intervals within 30 minutes after stimulation. In the control and placebo groups MPT measurements were recorded at similar time intervals. RESULTS: Difference scores, calculated from patients' baseline values, were analyzed by ANOVA for each of the three recording points. Although results showed a significant increase in MPT levels in all three stimulation groups when compared with their relative placebo (indicating a hypoalgesic effect), no differences were observed between the different modalities or HWT frequencies. Significant hypoalgesia continued for 5 minutes after stimulation. CONCLUSION: The findings showed that HWT and TENS provided localized hypoalgesia during stimulation and for up to 5 minutes after it. No frequency- or modality-specific effects were observed between the groups.

Adult↗
PubMed1998

Transcutaneous electrical nerve stimulation: effect on peripheral nerve conduction, mechanical pain threshold, and tactile threshold in humans.

OBJECTIVES: To investigate the effect of different transcutaneous electrical nerve stimulation (TENS) parameters on nerve conduction in the human superficial radial nerve and on peripheral mechanical pain threshold (MPT) and tactile threshold (TT), and to further the current knowledge of the neurophysiologic effects of TENS. STUDY DESIGN: Fifty healthy human subjects were randomly allocated in equal numbers to a control group or one of four TENS groups to receive electrical stimulation consisting of four combinations of TENS pulse durations (50microsec and 200microsec) and frequencies (4Hz and 110Hz). In the TENS groups, TENS was applied under double-blind conditions for 15 minutes over the superficial radial nerve in the dominant forearm. Over a 1-hour period, compound action potentials, MPT readings, and TT readings were recorded bilaterally. RESULTS: Only one combination of TENS parameters (110Hz, 200microsec) effected consistent changes in all of the variables assessed, ie, TENS produced a significant increase in negative peak latency while simultaneously increasing both MPT and TT. CONCLUSION: The findings from this study suggest that at least part of TENS-mediated hypoalgesia is a consequence of a direct peripheral effect of TENS, although a "central" effect may not be excluded.

Adult↗
PubMed1996

Localization of two potassium channel beta subunit genes, KCNA1B and KCNA2B.

The gating properties and current amplitudes of mammalian voltage-activated Shaker potassium channels are modulated by at least two associated beta subunits (Kv beta 1.1 and Kv beta 1.2). The human Kv beta 1.1 gene (KCNA1B) resides on chromosome 3, as indicated by somatic cell hybrid mapping. More precise localization of KCNA1B to 3q26.1 was obtained with fluorescence in situ hybridization (FISH) and was corroborated by PCR screening of the CEPH YAC library. The human Kv beta 1.2 gene (KCNA2B) resides on chromosome 1, as indicated by somatic cell hybrid mapping, and has been localized by FISH to 1p36.3.

Base Sequence↗
PubMed1995

Alternative splicing of the human Shaker K+ channel beta 1 gene and functional expression of the beta 2 gene product.

Mammalian voltage-activated Shaker K+ channels associate with at least three cytoplasmic proteins: Kv beta 1, Kv beta 2 and Kv beta 3. These beta subunits contain variable N-termini, which can modulate the inactivation of Shaker alpha subunits, but are homologous throughout an aldo-keto reductase core. Human and ferret beta 3 proteins are identical with rat beta 1 throughout the core while beta 2 proteins are not; beta 2 also contains a shorter N-terminus and has no reported physiological role. We report that human beta 1 and beta 3 are derived from the same gene and that beta 2 modulates the inactivation properties of Kv1.4 alpha subunits.

Alternative Splicing↗
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↗