Neuronal membrane hyperpolarization

Bupivacaine influx, leading to neuronal membrane hyperpolarization Anesthetic, binds to sodium channel, decreases sodium... 

Other mechanisms In addition to its action on calcium channels, valproic acid causes neuronal membrane hyperpolarization, possibly by enhancing K+ channel permeability. In addition to its actions on sodium channels and GABA-chloride channels, phenobarbital also acts as an antagonist at some glutamate receptors. Topiramate appears to block sodium channels and potentiate the actions of GABA and may also block glutamate receptors. 

The major inhibitory neurotransmitter in the cerebral cortex is y-aminobutyric acid (GABA). It attaches to neuronal membranes and opens chloride channels. When chloride flows into the neuron, it becomes hyperpolarized and less excitable. This mechanism is probably critical for shutting off seizure activity by controlling the excessive neuronal firing. Some antiepileptic drugs, primarily barbiturates and benzodiazepines, work by enhancing the action of GABA. 

As far as the biological action in Aplysia neurons of hepoxilin A3 and 12-kete is concerned, application of hepoxilin A3 to L14 neurons results in a marked membrane hyperpolarization, accompanied by an increased membrane ion conductance, while application of 12-kete to the same cells produced... 

Therefore, the activation of 5-HT1A receptors in the 5-HT cells by the endogenous transmitter or 5-HT1A receptor agonists increases K+ conductance, which hyperpolarizes the neuronal membrane (see below), thus inhibiting 5-HT cell firing (19-22) (see below) and reducing 5-HT release in the cell body area (23-27) and projection structures (24,25,28-30) (Fig. 1). 

The 5-HT1A receptors are coupled to potassium and calcium channels. Intracellular current-clamp recordings in slices containing the DR established that the 5-HT-mediated inhibition involved an increase in potassium conductance, which exhibits inward rectification (18,58). This induced a membrane hyperpolarization leading to a decrease in action potential frequency. Similar responses to 5-HT1A receptor activation have been reported in other neuronal types, such as hippocampal pyramidal cells (16,59) or 5-HT neurons of the caudal raphe nuclei (60). 

Fig. 2. Hyperpolarizing effects of 5-HT on the medial prefrontal cortex and hippocampal pyramidal neurons. (A) Bath application of 5-HT (30 pM) elicited a hyperpolarizing response that was blocked by BMY 7378 (3 pM). The lower trace shows that the selective 5-HT1A agonist 8-OH-DPAT (30 M) induced a membrane hyperpolarization comparable to that elicited by 5-HT (30 pM). Reproduced with permission from ref. 75. (B) Bath application of 5-carboxyamidotryptamine (5-CT) and 5-HT produced a similar membrane hyperpolarization in CA1 hippocampal pyramidal cells. The lower panels show the inability of 5-HT and 5-CT to elicit the hyperpolarizing response in presence of the 5-HT1A receptor antagonist WAY-100635. Reproduced with permission from ref. 76.

As far as is currently known, benzodiazepines and similar drugs (zopiclone, zolpidem) act by a single mechanism, interacting at the GABA receptor complex to enhance the ability of GABA to open a chloride ion channel and thereby hyperpolarize the neuronal membrane. It is usual, therefore, to classify benzodiazepines, and recommend their clinical use, on the basis of their duration of action or their half-life. While this is without doubt a useful classification, it is simplistic and does not take into account other important pharmacokinetic factors. 

The pharmacological mechanisms for the CNS depressant actions of ethanol are complex and incompletely understood, but probably involve both enhancement of major inhibitory neurons and impairment of excitatory neurons. The principal CNS inhibitory neuronal system is mediated by the neurotransmitter y-aminobutyric acid (GABA). When GABA binds to its postsynaptic receptor subtype GABAa, this oligomeric ion-gated complex opens to allow inward flux of Cl, leading to membrane hyperpolarization... 

Cyclic AMP has been implicated in synaptic transmission due to its actions on a number of important synaptic and neuronal events, such as membrane permeability, synaptic membrane phosphorylation, neurotransmitter synthesis, and cell growth and differentiation. As pointed out earlier, neurotransmitter-receptor interactions can result in direct physical perturbations of the membrane with consequent alterations in membrane permeability to specific ions. This effect is particularly the case when the ionophore is located near the receptor. However, if the ionic channel is distant from the receptor, mechanisms such as phosphorylation can result in an alteration of channel permeability. Cyclic AMP is known to lead to a hyperpolarization of neurons in a number of brain regions such as the cerebral cortex, the caudate nucleus, the peripheral paravertebral sympathetic ganglia, the cerebellar cortex, and the hippocampus. Although it has been hypothesized that this hyperpolarization is the consequence of the phosphorylation of specific neuronal membrane proteins, the relatively short duration of hyperpolarization... 

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