Sensitivity of AMPA receptor channel to calcium oscillations: A computational study

We used a computational model of biochemical pathways that are involved in the phosphorylation/dephosphorylation of AMPA receptor to study the receptor responses to calcium oscillations. In the model, the biochemical pathways are assumed to be located immediately under the postsynaptic membrane and we included three states of AMPA receptor: dephosphorylated, and phosphorylated in one or in two sites. To characterize the effects of calcium oscillations on the AMPA receptor, we exposed the model to stimuli with three varying parameters, namely frequency, number of pulses and calcium spike duration. Our model showed sensitivity to all of these three parameters. © 2002 Elsevier Science B.V. All rights reserved.

Central nitric oxide modulates hindquarter vasodilation elicited by AMPA receptor stimulation in the NTS of conscious rats

Microinjection of S-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the nucleus of the solitary tract (NTS) of conscious rats causes hypertension, bradycardia, and vasoconstriction in the renal, mesenteric, and hindquarter vascular beds. In the hindquarter, the initial vasoconstriction is followed by vasodilation with AMPA doses >5 pmol/100 nl. To test the hypothesis that this vasodilation is caused by activation of a nitroxidergic pathway in the NTS, we examined the effect of pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10 nmol/100 nl, microinjected into the NTS) on changes in mean arterial pressure, heart rate, and regional vascular conductance (VC) induced by microinjection of AMPA (10 pmol/100 nl in the NTS) in conscious rats. AMPA increased hindquarter VC by 18 ± 4%, but after pretreatment with L-NAME, AMPA reduced hindquarter VC by 16 ± 7% and 17 ± 9% (5 and 15 min after pretreatment, P < 0.05 compared with before pretreatment). Pretreatment with L-NAME reduced AMPA-induced bradycardia from 122 ± 40 to 92 ± 32 beats/min but did not alter the hypertension induced by AMPA (35 ± 5 mmHg before pretreatment, 43 ± 6 mmHg after pretreatment). Control injections with D-NAME did not affect resting values or the response to AMPA. The present study shows that stimulation of AMPA receptors in the NTS activates both vasodilatatory and vasoconstrictor mechanisms and that the vasodilatatory mechanism depends on production of nitric oxide in the NTS. Copyright © 2006 the American Physiological Society.

Toward an Explanation of the Genesis of Ketamine-Induced Perceptual Distortions and Hallucinatory States

The NMDA receptor (NMDAR) channel has been proposed to function as a coincidence-detection mechanism for afferent and reentrant signals, supporting conscious perception, learning, and memory formation. In this paper we discuss the genesis of distorted perceptual states induced by subanesthetic doses of ketamine, a well-known NMDA antagonist. NMDAR blockage has been suggested to perturb perceptual processing in sensory cortex, and also to decrease GABAergic inhibition in limbic areas (leading to an increase in dopamine excitability). We propose that perceptual distortions and hallucinations induced by ketamine blocking of NMDARs are generated by alternative signaling pathways, which include increase of excitability in frontal areas, and glutamate binding to AMPA in sensory cortex prompting Ca++ entry through voltage-dependent calcium channels (VDCCs). This mechanism supports the thesis that glutamate binding to AMPA and NMDARs at sensory cortex mediates most normal perception, while binding to AMPA and activating VDCCs mediates some types of altered perceptual states. We suggest that Ca++ metabolic activity in neurons at associative and sensory cortices is an important factor in the generation of both kinds of perceptual consciousness.

O óxido nítrico (NO) no controle neural da pressão arterial: Modulação da transmissão glutamatérgica no NTS

The neuromodulatory effect of nitric oxide (NO) on glutamatergic transmission within the NTS related to cardiovascular regulation has been widely investigated. Activation of glutamatergic receptors in the NTS stimulates the production and release of NO and other nitrosyl substances with neurotransmitter/neuromodulator properties. The presence of NOS, including the protein nNOS and its mRNA in vagal afferent terminals in the NTS and nodose ganglion cells suggest that NO can act on glutamatergic transmission. We previously reported that iontophoresis of L-NAME on NTS neurons receiving vagal afferent inputs significantly decreased the number of action potentials evoked by iontophoretic application of AMPA. In addition, iontophoresis of the NO donor papaNONOate enhanced spontaneous discharge and the number of action potentials elicited by AMPA, suggesting that NO could be facilitating AMPA-mediated neuronal transmission within the NTS. Furthermore, the changes in renal sympathetic discharge during activation of baroreceptors and cardiopulmonary receptors involve activation of AMPA and NMDA receptors in the NTS and these responses are attenuated by microinjection of L-NAME in the NTS of conscious and anesthetized rats. Cardiovascular responses elicited by application of NO in the NTS are closely similar to those obtained after activation of vagal afferent inputs, and L-glutamate is the main neurotransmitter of vagal afferent fibers. In this review we discuss the possible neuromodulatory mechanisms of central produced/released NO on glutamatergic transmission within the NTS.

Biomolecular information, brain activity and cognitive functions

Molecular neurobiology has provided an explanation of mechanisms supporting mental functions as learning, memory, emotion and consciousness. However, an explanatory gap remains between two levels of description: molecular mechanisms determining cellular and tissue functions, and cognitive functions. In this paper we review molecular and cellular mechanisms that determine brain activity, and then hypothetize about their relation with cognition and consciousness. The brain is conceived of as a dynamic system that exchanges information with the whole body and the environment. Three explanatory hypotheses are presented, stating that: a) brain tissue function is coordinated by macromolecules controlling ion movements, b) structured (amplitude, frequency and phase-modulated) local field potentials generated by organized ionic movement embody cognitive information patterns, and c) conscious episodes are constructed by a large-scale mechanism that uses oscillatory synchrony to integrate local field patterns. © by São Paulo State University.