Depolarization membranes

Local anesthetics produce anesthesia by blocking nerve impulse conduction in sensory, as well as motor nerve, fibers. Nerve impulses are initiated by membrane depolarization, effected by the opening of a sodium ion channel and an influx of sodium ions. Local anesthetics act by inhibiting the channel s opening they bind to a receptor located in the channel s interior. The degree of blockage on an isolated nerve depends not only on the amount of dmg, but also on the rate of nerve stimulation (153—156). 

Big-conductance Ca2+ sensitive K+ (BKca) channels are activated by calcium surge and membrane depolarization. BKCa channels are specifically blocked by iberiotoxin and less selectively by charybdotoxin. BKCa channels are composed of pore-forming a and auxiliary (3 subunits. Both BKCa,a andBKca, 3 subunits as well as their efficient coupling in the heteromultimeiic formation of BKca channel complexes are important for the function of BKCa channels. 

Voltage-gated Ca2+ channels are Ca2+-selective pores in the plasma membrane of electrically excitable cells, such as neurons, muscle cells, (neuro) endocrine cells, and sensory cells. They open in response to membrane depolarization (e.g., an action potential) and permit the influx of Ca2+ along its electrochemical gradient into the cytoplasm. 

Inward Rectification refers to decreased conductance upon membrane depolarization. In classical inward rectifier K+ channels, rectification is strong and currents rapidly decline at membrane potentials positive to the reversal potential, in contrast to other Kir channels in which rectification is weak and currents decline only gradually at potentials positive to the reversal potential. 

TRPM4 also known as the Ca2+-activated nonselective cation (CAN-) channel, mediates cell membrane depolarization in many excitable and nonexcitable cells. 

Voltage-dependent sodium channels are a family of membrane proteins that mediate rapid Na+ influx, in response to membrane depolarization to generate action potentials in excitable cells. 

Ca may activate phospholipase A2 and cause production of lyso-lipids and fatty acids. In addition, ionic fluxes across the membrane occur, leading to pH changes and membrane depolarization. It is not clear how these other responses are initiated, but there may be direct G-protein links to effector systems such as phospholipase A2 or ionic channels. 

Membrane depolarization can be measured by members of a class of fluorophores (commonly referred to as the carbocyanine dyes) which have been designed to partition into the membrane, where their orientation and spectral properties change with changes in the electrochemical gradient across the membrane (18). 3,3 -dipropyl-... 

Figure 2. Dose-response curve of membrane depolarization as a function of PbTx-3 concentration (7). Data from a total of 22 axons were pooled each axon received only one dose. Data are plotted as means of depolarization amplitudes. TTie solid line is a theoretical 3rd order fit with an ED.q of 1.5 nM, maximum observed depolarization of 30 mV, and a Hill s coefficient of 2.

The lipid-soluble toxins (veratridine, batrachotoxin, aconitine, grayanotoxins). These toxins cause persistent activation of Na channels, i.e., their permanent opening and hence membrane depolarization 56-58). 

CTx that has been purified from muscles of Gymnothorax javanicus stimulates the release of neurotransmitters such as 7-aminobutyric acid and dopamine from rat brain nerve terminals. It causes a membrane depolarization of mouse neuroblastoma cells and, under appropriate conditions, it creates spontaneous oscillations of... 

Palytoxin (PTX) is one of the most potent marine toxins known and the lethal dose (LD q) of the toxin in mice is 0.5 Mg/kg when injected i.v. The molecular structure of the toxin has been determined fully (1,2). PTX causes contractions in smooth muscle (i) and has a positive inotropic action in cardiac muscle (4-6). PTX also induces membrane depolarization in intestinal smooth (i), skeletal (4), and heart muscles (5-7), myelinated fibers (8), spinal cord (9), and squid axons (10). PTX has been demonstrated to cause NE release from adrenergic neurons (11,12). Biochemical studies have indicated that PTX causes a release of K from erythrocytes, which is followed by hemolysis (13-15). The PTX-induced release of K from erythrocytes is depress by ouabain and that the binding of ouabain to the membrane fragments is inhibited by PTX (15). 

The Ca channels that have been the most extensively studied are the voltage-dependent Ca channels. These channels are usually found in plasma or transverse tubule membranes. Voltage-dependent Ca channels open in response to an appropriate membrane depolarization. Several different types of voltage-dependent Ca channels have been described and are characterized by differences in their activation and inactivation sensitivities to voltage, their kinetic properties, and their sensitivities to activation or inhibition by a variety of pharmacological agents. 

As more EPSPs add together, the membrane depolarizes closer to threshold until an action potential is generated. Although temporal summation is illustrated in Figure 5.2 with the summation of relatively few EPSPs, in actuality, addition of up to 50 EPSPs may be necessary to reach threshold. Because a presynaptic neuron may generate up to 500 action potentials per... 

Ion channels are macromolecular complexes that form aqueous pores in the lipid membrane. We have learned much about ion channel function from voltage clamp and patch clamp studies on channels still imbedded in native cell membranes [1-6, 8]. A diversity of channel types was discovered in the different cells in the body, where the repertoire of functioning channels is adapted to the special roles each cell plays [5]. The principal voltage-gated ones are the Na+, K+ and Ca2+ channels, and most of these are opened by membrane depolarizations. Figure 6-5A summarizes the major functional properties of a voltage-gated... 

Na+ channels are primarily a single family. There are ten human genes encoding voltage-gated Na+ channels (Table 6-2), and at least nine of the ten encode members of a single family (Navl.l-1.9) [38], These Na+ channels are expressed in different tissues and cells but their function is almost always to initiate action potentials in response to membrane depolarization. 

CaMKI and CaMKII) Dynamin-1 GTPase required for endocytosis that is phosphorylated by protein kinase C and dephosphorylated by calcineurin upon membrane depolarization and binds to AP2. Important for budding and fusion pore closure. 

Membrane depolarization typically results from an increase in Na+ conductance. In addition, mobilization of intracellular Ca2+ from the endoplasmic or sarcoplasmic reticulum and the influx of extracellular Ca2+ appear to be elicited by ACh acting on muscarinic receptors (see Ch. 22). The resulting increase in intracellular free Ca2+ is involved in activation of contractile, metabolic and secretory events. Stimulation of muscarinic receptors has been linked to changes in cyclic nucleotide concentrations. Reductions in cAMP concentrations and increases in cGMP concentrations are typical responses (see Ch. 21). These cyclic nucleotides may facilitate contraction or relaxation, depending on the particular tissue. Inhibitory responses also are associated with membrane hyperpolarization, and this is a consequence of an increased K+ conductance. Increases in K+ conductance may be mediated by a direct receptor linkage to a K+ channel or by increases in intracellular Ca2+, which in turn activate K+ channels. Mechanisms by which muscarinic receptors couple to multiple cellular responses are considered later. 

There is considerable evidence that the release of 5-HT occurs by exocytosis, i.e. by the discharge from the cell of the entire content of individual storage vesicles. First, 5-HT is sufficiently ionized at physiological pH so that it does not cross plasma membranes by simple diffusion. Second, most intraneuronal 5-HT is contained in storage vesicles and other contents of the vesicle including SPB are released together with serotonin. By contrast, cytosolic proteins do not accompany electrical stimulation-elicited release of 5-HT. Third, the depolarization-induced release of 5-HT occurs by a calcium-dependent process indeed, it appears that the influx of extracellular calcium ions with or without membrane depolarization can increase the release of 5-HT. Calcium stimulates the fusion of vesicular membranes with the plasma membrane (see Chs 9,10). 

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