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P Chavis

Publications and source records attributed to P Chavis.

16 recordsLinked to original sources
PubMed2001

Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapse.

Coordinated signalling between presynaptic terminals and their postsynaptic targets is essential for the development and function of central synapses. In addition to diffusible molecules, this bidirectional flow of information could involve direct interactions through cell-adhesion molecules. Here, we show that one class of cell-adhesion molecule, the integrins, are required for the functional maturation of hippocampal synapses in vitro. At immature synapses, a high probability of glutamate release (Pr) was correlated with the expression of postsynaptic NMDA (N-methyl-D-aspartate) receptors containing the NR2B subunit. The activity-dependent reduction in Pr and a switch in the subunit composition of synaptic NMDA receptors was prevented by chronic blockade with peptides containing the integrin-binding site Arg-Gly-Asp (RGD), or by a functional antibody against the beta3 integrin subunit. Active synapses, monitored by the uptake of antibodies against the intraluminal domain of synaptotagmin I, also had beta3 subunit immunoreactivity. Our results provide evidence that integrin-mediated signalling is essential for the orchestrated maturation of central excitatory synapses.

Animals↗
PubMed2000

Complex interactions between mGluRs, intracellular Ca2+ stores and ion channels in neurons.

Metabotropic glutamate receptors (mGluRs) can increase intracellular Ca2+ concentration via Ins(1,4,5)P3- and ryanodine-sensitive Ca2+ stores in neurons. Both types of store are coupled functionally to Ca2+-permeable channels found in the plasma membrane. The mGluR-mediated increase in intracellular Ca2+ concentration can activate Ca2+-sensitive K+ channels and Ca2+-dependent nonselective cationic channels. These mGluR-mediated effects often result from mobilization of Ca2+ from ryanodine-sensitive, rather than Ins(1,4, 5)P3-sensitive, Ca2+ stores, suggesting that close functional interactions exist between mGluRs, intracellular Ca2+ stores and Ca2+-sensitive ion channels in the membrane.

Animals↗
PubMed1999

Optic disc elevation in Down syndrome.

BACKGROUND: Optic disc elevation associated with Down syndrome is an uncommon phenomenon and raises the suspicion of an intracranial space-occupying lesion, thus necessitating the consideration of invasive and noninvasive investigations. METHOD OF STUDY: Four patients with Down syndrome and optic disc elevation without an underlying intracranial pathology are reported. Thorough ophthalmological and neuroradiological investigations were performed on each patient. Mild hyperopia occurred in three patients and myopia in one. CONCLUSIONS: We believe that in most Down syndrome patients with disc elevation, fluorescein angiography and/or clinical follow-up may be sufficient.

Child↗
PubMed1998

Visualization of cyclic AMP-regulated presynaptic activity at cerebellar granule cells.

Adenylyl cyclase (AC) modulation of vesicular cycling was visualized at cultured cerebellar granule cell synapses using the sequential uptake of antibodies directed against the intraluminal domain of synaptotagmin I. Vesicle recycling due to spontaneous transmitter release in the absence of action potentials was increased by the AC/protein kinase A (PKA) activators forskolin and CPT-cAMP. These effects were blocked by the PKA inhibitor Rp-cAMPs. Cyclic AMP elevation also induced new cycling at previously silent sites. Activation of L-AP4-sensitive mGluR reduced the cAMP/PKA enhancement at preexisting synapses downstream of both AC and calcium channels. Modulation of the turnover and the number of vesicular release sites provide one mechanism that may underlie cAMP-dependent cerebellar long-term potentiation.

Action Potentials↗
PubMed1998

Modulation of big K+ channel activity by ryanodine receptors and L-type Ca2+ channels in neurons.

As metabotropic glutamate receptor type 1 (mGluR1) is known to couple L-type Ca2+ channels and ryanodine receptors (RyR, Chavis et al., 1996) in cerebellar granule cells, we examined if such a coupling could activate a Ca2+-sensitive K+ channel, the big K+ (BK) channel, in cultured cerebellar granule cells. We observed that (+/-)-1-amino-cyclopentane-trans-1,3-dicarboxylic acid (t-ACPD) and quisqualate (QA) stimulated the activity of BK channels. On the other hand, (2S, 3S, 4S)-alpha-carboxycyclopropyl-glycine (L-CCG-I) and L-(+)-2-amino-4-phosphonobutyrate (L-AP4) had no effect on BK channels, indicating a specific activation by group I mGluRs. Group I mGluRs stimulation of the basal BK channel activity was mimicked by caffeine and both effects were blocked by ryanodine and nifedipine. Interestingly, carbachol stimulated BK channel activity but through a pertussis toxin (PTX)-sensitive pathway that was independent of L-type Ca2+ channel activity. Our report indicates that unlike the muscarinic receptors, group I mGluRs activate BK channels by mobilizing an additional pathway involving RyR and L-type Ca2+ channels.

Animals↗
PubMed1996

Functional coupling between ryanodine receptors and L-type calcium channels in neurons.

In skeletal muscle, L-type Ca2+ channels act as voltage sensors to control ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum. It has recently been demonstrated that these ryanodine receptors generate a retrograde signal that modifies L-type Ca2+ -channel activity. Here we demonstrate a tight functional coupling between ryanodine receptors and L-type Ca2+ channel in neurons. In cerebellar granule cells, activation of the type-1 metabotropic glutamate receptor (mGluR1) induced a large, oscillating increase of the L-type Ba2+ current. Activation occurred independently of inositol 1,4,5-trisphosphate and classical protein kinases, but was mimicked by caffeine and blocked by ryanodine. The kinetics of this blockade were dependent on the frequency of Ba2+ current stimulation. Both mGluR1 and caffeine-induced increase in L-type Ca2+ -channel activity persisted in inside-out membrane patches. In these excised patches, ryanodine suppressed both the mGluR1- and caffeine-activated L-type Ca2+ channels. These results demonstrate a novel mechanism for Ca2+ -channel modulation in neurons.

Animals↗
PubMed1995

Modulation of calcium channels by metabotropic glutamate receptors in cerebellar granule cells.

We investigated the mechanisms by which metabotropic glutamate receptors (mGluRs) modulate specific Ca2+ channels in cerebellar granule cells. A large fraction of the current in granule cells is carried by L- and Q-type Ca2+ channels (about 26% each), whereas N- and P-type contribute proportionally less to the global current (9 and 15%, respectively). l-Aminocyclopentane-dicarboxylate (t-ACPD), (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCGI) and (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG], but not L(+)-2-amino-4-phosphonobutyrate (L-AP4) reduced the Ca2+ current amplitude. The t-ACPD-induced inhibition was fully antagonized by (+/-)-methyl-4-carboxyphenylglycine [(+/-)-MCPG] and blocked by pertussis toxin (PTX). These results are consistent with inhibitory response mediated by mGluR2/R3. The use of specific Ca2+ channel blockers provided evidence that mGluR2/R3 inhibited both L- and N-type Ca2+ currents. In PTX-treated cells, Glu or t-ACPD, but not L-CCGI or L-AP4, increased the Ca2+ current. Consistent with the activation of mGluR1, the antagonists (+)-MCPG and (S)-4C3HPG prevented the facilitation of Ca2+ current produced by t-ACPD. The mGluR1-activated facilitation was completely blocked by nimodipine, indicating that L-type Ca2+ currents were selectively potentiated.

Animals↗
PubMed1995

Familial childhood primary lateral sclerosis with associated gaze paresis.

Three children from consanguineous parents began losing the ability to walk in late infancy. Despite chronically progressive weakness leading to wheelchair dependence by adolescence and later loss of motor speech production, intellect remained preserved. Examination revealed upper motor neuron findings of pseudobulbar palsy and spastic quadriplegia, without dementia, cerebellar, extrapyramidal or sensory signs. In addition they exhibited a diffuse conjugate saccadic gaze paresis, especially severe on down-gaze. CT and MRI scans of brain and spinal cord, EEGs, visual and brainstem auditory evoked potentials, CSF examinations, enzyme assays for lysosomal storage diseases, blood amino acids and urine organic acids were all normal. Cortical somatosensory evoked potentials were poorly configured in two of the patients, though they had normal central conduction. EMG showed no signs of denervation. Nerve conduction studies showed normal peripheral motor and sensory conduction velocities. Transcranial magnetic stimulation of the brain elicited no motor-evoked potentials. Despite the lack of neuropathological confirmation, the clinical course and neurophysiologic data strongly support the diagnosis of a familial (autosomal recessive) primary lateral sclerosis (PLS).

Adolescent↗
PubMed1995

Facilitatory coupling between a glutamate metabotropic receptor and dihydropyridine-sensitive calcium channels in cultured cerebellar granule cells.

The effect of metabotropic glutamate receptor activation on Ca dihydropyridine (DHP)-sensitive channels recorded in the presence of 1 microM Bay K 8644 was examined on cultured cerebellar granule cells using the patch-clamp technique in the cell-attached configuration. Bath-applied agonist (trans-ACPD, 1S,3R-, and 1R,3S-ACPD isomers, and glutamate or quisqualate in the presence of CPP and CNQX) evoked an increase in Ca channel activity with a variable latency of 8.9 +/- 8.6 sec in 40% of the recorded cells. Neither L-CCG1, L-AP3, L-AP4, nor AMPA or NMDA activated Ca channels. Two dihydropyridine-sensitive channels present in this cell type were activated by trans-ACPD: the classical 24 pS L-type channel and a smaller-conductance 7 pS channel. The effect was shown to be mediated by neither intracellular Ca2+ nor a pertussis toxin (PTX)-sensitive G protein. Interestingly treatment with BAPTA-AM increased the number of responding patches and the activity was more sustained throughout the drug application. After overnight PTX treatment, activation of the Ca channels persisted even after washout of the agonist. These results indicate that mGluR1/mGluR5 probably mediate the facilitation of dihydropyridine-sensitive Ca channels.

Animals↗
PubMed1994

The metabotropic glutamate receptor types 2/3 inhibit L-type calcium channels via a pertussis toxin-sensitive G-protein in cultured cerebellar granule cells.

Modulation of Ca2+ channels by metabotropic glutamate receptors (mGluRs) was investigated in cerebellar granule cells using the cell-attached configuration of the patch-clamp technique. Experiments were performed in the absence of external Ca2+ and Ba2+ was used as charge carrier. Bath applied glutamate or (1S,3R) trans-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R t-ACPD) inhibited Ca2+ channels activated by depolarizing pulses. These channels were sensitive to dihydropyridines and displayed a 23 pS conductance. This effect was mimicked by (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I), a selective agonist of mGluR2/R3 receptors, but not by quisqualate at a concentration that stimulated inositol phosphate (InsP) synthesis, showing that mGluR1 and mGluR5 did not participate to this mechanism. The phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX), did not alter the action of the mGluR agonists and biochemical measurements showed that 1S,3R t-ACPD, in the presence of IBMX, decreased cAMP formation in such a small amount that this change could not explain the almost complete inhibition of the channel activity observed under similar experimental conditions. Moreover, whole-cell recorded L-type Ca2+ currents were inhibited by L-CCG-I, in the presence of 1 mM intracellular cAMP. These observations were consistent with the hypothesis that cyclic nucleotide second messengers were not involved in this effect. Neither the protein kinase C activator phorbol-12,13-dibutyrate (PDBU) nor the phosphatase inhibitor okadaic acid affected the action of 1S,3R t-ACPD. The inhibitory action of 1S,3R t-ACPD was abolished by pertussis toxin (PTX). These results suggest that mGluR2 or mGluR3 receptors suppress the activity of L-type Ca2+ channels by a mechanism involving Gi or G(o) proteins. A likely direct effect of G-proteins on the channels is discussed.

Animals↗
PubMed1981

Recurrent retinal ischemia beyond cervical carotid occlusions: clinical-angiographic correlations and therapeutic implications.

Seventeen patients with persistent amaurosis fugax ipsilateral to angiographically documented internal carotid artery (ICA) occlusions in the neck have been treated by the authors over the past 5 years. Complete cerebral arteriography in each case demonstrated that the symptomatic ophthalmic artery was perfused exclusively by the ipsilateral external carotid artery (ECA), which invariably had an obstructive and/or ulcerative lesion and its origin, and/or an adjacent residual "stump" of the occluded ICA. In nine patients, retinal artery branch emboli were visible on funduscopy. One patient had angiographic evidence of intracranial embolization via the ophthalmic artery from the ECA. Although ipsilateral superficial temporal-muscle cerebral artery anastomosis in one patient, and endarterectomy of a contralateral carotid stenosis in another patient, failed to relieve symptoms, endarterectomy of the ECA with resection of the "stump" of the occluded ICA effectively terminated symptoms in 10 of 11 patients. Anticoagulant drug therapy promptly abolished symptoms in four nonsurgical patients as well as in two patients with failed operations. It is concluded that recurrent retinal ischemia beyond cervical carotid occlusions frequently results from microembolism via the ipsilateral ECA. Patients with this mechanism of postocclusion recurrent ischemia can be identified on the basis of clinical history, ophthalmological examinations, and complete cerebral arteriography. Termination of embolic phenomena should be the major treatment goal in these individuals, and ECA endarterectomy is recommended. Anticoagulant drugs are an effective alternative treatment in patients who are poor surgical risks.

Adult↗
PubMed1980

Carotid ligation for recurrent ischemia due to inaccessible carotid obstruction. Examination of the rationale of this treatment.

Experiences with a patient with symptomatic obstruction to the carotid artery in its petrous segment are described. In spite of the severe stenosis of this vessel, complete arteriography demonstrated excellent perfusion of the symptomatic eye and hemisphere and an ample collateral reserve. Funduscopy confirmed the clinical impression that recurrent retinal and hemispheric ischemia in this patient was the result of microembolism rather than intracranial hemodynamic insufficiency. Consequently, extracranial-intracranial (EC-IC) bypass was believed to offer little benefit to this patient. Abrupt ligation of the internal carotid artery in the neck proved to be an effective method for arresting the embolic discharge from this vessel's inaccessible obstruction, and resulted in prompt and complete relief of ischemic symptoms. It is concluded that identifying the mechanism(s) responsible for recurrent ischemia past uncorrectable carotid obstructions is of paramount importance in order to establish the most appropriate treatment(s). Carotid occlusion is an effective surgical remedy for terminating microembolism from this vessel when it is diseased and incompletely obstructed, and should be considered in selected patients. The importance of angiographic evaluation of naturally occurring EC-IC anastomotic connections in addition to the assessment of intracranial collateral reserves in cases of carotid occlusion is also emphasized.

Brain Ischemia↗
PubMedDate not supplied

Dilated episcleral arteries--a significant physical finding in assessment of patients with cerebrovascular insufficiency.

Dilated episcleral vessels associated with ipsilateral internal carotid artery occlusions have been previously reported though not widely appreciated. These ocular changes have been presumed to be manifestations of ocular ischemia. The authors have recently encountered this sign in seven patients and in none was there evidence of ocular ischemia. In addition to an ipsilateral internal carotid artery occlusion, arteriograms demonstrated that the major source of blood supply to the homolateral cerebral hemisphere was by retrograde flow through markedly enlarged ophthalmic arteries filled in retrograde fashion from dilated external carotid collateral channels in the orbit. This association of dilated episcleral arteries as a sign of increased orbital blood flow and the major source of collateral blood supply to the homolateral cerebral hemisphere has not been previously reported. We reemphasize the importance of a careful examination of the episcleral vessels in patients suspected of having internal carotid artery occlusions.

Carotid Arteries↗
PubMedDate not supplied

The effect of postural changes upon the ankle arterial perfusion pressure.

The normal arterial blood pressure at the ankle, (AP), right brachial arterial pressure (RBP) and pressure index (PI) were investigated in 50 healthy young volunteers under basal conditions and during certain positions of the legs, utilizing Doppler ultrasound flow determination and standard size blood pressure cuff. The mean AP was 10 mm Hg higher than the mean RBP in 76 instances but AP was smaller than RBP in 24 out of 100 investigated lower extremities. Mean PI was 1.069+/-0.158. There was no statistically significant difference between PI of heavier and leaner patients although increased weight was associated with a significantly higher brachial and ankle arterial pressure. Departure of the lower extremity from the horizontal position resulted in AP changes explained by gravitational effects. If the new posture was maintained, the new AP persisted, thus indicating an absence of significant corrective circulatory adaptation to the posture changes. Extreme flexion of hip and knee joints resulted in a marked decrease of AP and PI, suggesting arterial kinking. This change was not affected by the weight:height ratio of the subject. It is concluded, therefore, that the presence of a greater amount of periarterial soft tissues does not significantly prevent arterial kinking. These tensional shifts indicate changes of flow pattern occurring in normal subjects during extreme flexion. Even more marked shifts can be anticipated in arteriosclerotic patients under similar circumstances.

Adult↗