Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study begins to explore possible mechanisms underlying the role of GABAB receptors in absence seizures in lethargic (lh/lh) mice. To test the hypothesis that alterations intrinsic to the GABAB receptor underlie enhanced synaptic activation of these receptors in absence seizures, we measured GABA-displaceable [3H]baclofen binding to neocortical plasma membranes prepared from lh/lh and wild (+/+) age-matched congenic mice. The number (Bmax) of binding sites was significantly greater (20%) in lh/lh (4.2 pmol/mg protein, n = 43 pairs, P < 0.02) than in +/+ mice (3.3 pmol/mg protein) in an age-independent manner. Interestingly, the subset of lh/lh mice with greater seizure frequency (40-70 seizures/15 min, measured by bipolar electrodes implanted into neocortex; n = 11) had a significantly greater Bmax (P < 0.003) than the subset with lower seizure frequency (1-10 seizures/15 min; n = 11). The equilibrium dissociation constant (Kd) was unchanged (60 nM in both). The Kd of both strains was inhibited to an equal degree by the nonhydrolysable GTP analogue 5'-guanylimido-diphosphate [Gpp(NH)p]. The increased number of GABAB binding sites was selective, because binding to NMDA sites ([3H]glutamate binding) and to GABAA sites ([3H]muscimol binding) was not significantly different in the two strains. These data suggest that the increased number of GABAB receptors in lh/lh mice underlies enhanced synaptic activation of these receptors. Together with evidence that GABAB receptor activation can produce disinhibition, our data support a role for GABAB receptors in the expression of absence seizures in lh/lh mice.
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PMID:Increased number of GABAB receptors in the lethargic (lh/lh) mouse model of absence epilepsy. 838 8

1. The aim of this study was to investigate some of the cellular mechanisms involved in the effects caused by changes in extracellular Ca2+ concentration ([Ca2+](o)). 2. Current- and voltage-clamp experiments were carried out on acutely isolated thalamic neurons of rats. 3. Increasing [Ca2+](o) alone induced a transition of the discharge from single spike to burst mode in isolated current-clamped neurons. 4. Increasing [Ca(2+)](o) caused the voltage-dependent characteristics of the low voltage-activated (LVA) transient Ca2+ currents to shift towards positive values on the voltage axis. Changing [Ca2+](o) from 0.5 to 5 mM caused the inactivation curve to shift by 21 mV. 5. Extracellular Ca2+ blocked a steady cationic current. This current reversed at -35 mV, was scarcely affected by Mg2+ and was completely blocked by the non-selective cation channel inhibitor gadolinium (10 microM). The effect of [Ca2+](o) was mimicked by 500 microM spermine, a polyamine which acts as an agonist for the Ca(2+)-sensing receptor, and was modulated by intracellular GTP-gamma-S. 6. At the resting potential, both the voltage shift and the block of the inward current removed the inactivation of LVA calcium channels and, together with the increase in the Ca2+ driving force, favoured a rise in the low threshold Ca2+ spikes, causing the thalamic firing to change to the oscillatory mode. 7. Our data indicate that [Ca2+](o) is involved in multiple mechanisms of control of the thalamic relay and pacemaker activity. These findings shed light on the correlation between hypercalcaemia, low frequency EEG activity and symptoms such as sleepiness and lethargy described in many clinical papers.
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PMID:Changes in extracellular Ca2+ can affect the pattern of discharge in rat thalamic neurons. 1150 56

Rabphilin, a putative rab effector, interacts specifically with the GTP-bound form of the synaptic vesicle-associated protein rab3a. In this study, we define in vivo functions for rabphilin through the characterization of mutants that disrupt the Caenorhabditis elegans rabphilin homolog. The mutants do not display the general synaptic defects associated with rab3 lesions, as assayed at the pharmacological, physiological, and ultrastructural level. However, rabphilin mutants exhibit severe lethargy in the absence of mechanical stimulation. Furthermore, rabphilin mutations display strong synergistic interactions with hypomorphic lesions in the syntaxin, synaptosomal-associated protein of 25 kDa, and synaptobrevin soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) genes; double mutants were nonresponsive to mechanical stimulation. These synergistic interactions were independent of rab3 function and were not observed in rab3-SNARE double mutants. Our data reveal rab3-independent functions for rabphilin in the potentiation of SNARE function.
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PMID:Rabphilin potentiates soluble N-ethylmaleimide sensitive factor attachment protein receptor function independently of rab3. 1171 59