Na+ influx

An increase in [Na+]j can also regulate the Na+/Ca2+ exchanger. In particular, when intracellular Na+ increases, it binds to the transport site of the exchanger molecule, and after this Na+ influx, an inactivation process of the exchanger occurs. This inactivation process, very similar to the phenomenon occurring in voltage-dependent ionic channels, is named... 

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. 

The sodium channels are very selective for Na+ over K+, allowing Na+ influx down the electrochemical gradient to generate positive membrane potentials. The sodium channels are also permeable to Li+ and NH4+. The narrowest portion of the channel pore is estimated to be rectangular (3.1 x 5.2 A). 

Figure 3. Concentration dependence of the stimulation of Na influx by PbTx-3 (4). Synaptosomes were pre-incubated for 30 min with indicated concentrations of PbTx-3 in the presence of aconitine. Influx is plotted as specific influx, points representing means of triplicate determinations.

Na Influx Studies. Na influx was monitored according to the procedure of Owen and Villereal (34), with some modifications. Cells were seeded onto 60-mm culture dishes, grown, and serum starved as described for the assays above. The cells were washed with incubation media and incubated in 3 ml of the appropriate agent at 37 C. After incubation the cells were rapidly washed in ice cold 0.1 mM MgCL and extracted with 5% TCA/0.5% KNO3 for sodium determination or 0.2% SDS for protein determination. Sodium concentration was measured using a Varian Model 275 Atomic Absorption Spectrophotometer. Protein was determined fluorimetrically. 

Because these results suggest that extracellular Na is required for inhibition of EGF binding by palytoxin in these cells, we determined if palytoxin caused Na influx in Swiss 3T3 cells. When Na influx was monitored at an early time point (7 min), it was found that palytoxin causes an influx of Na and that the rate of Na influx is dose dependent (Figure 6). In parallel with its effect on EGF binding, palytoxin at different doses increases intracellular Na to the same final level (42). Although Na influx occurs prior to the inhibition of EGF binding, these results and the apparent Na dependence of the palytoxin effect suggest a role for Na in the action of palytoxin on the EGF receptor. 

Figure 6. Effect of palytoxin on the rate of Na influx in Swiss 3T3 cells. Confluent quiescent Swiss 3T3 cells were incubated for 37 C for 7 min in incubation media containing 0.1 pM PTX, 1.1 pM PTX, or 11 pM PTX. Intracellular Na was determined as described in the Experimental section. Data points represent the mean of quadruplicate points.

Na and Ca Influx. PTX caused a concentration-dependent increase in Na and Ca influxes into PC12 cells at concentrations of 10" to 10" M and 10" to 10" M, respectively. The PTX-induced Ca influx was markedly inhibited by Co but not by verapamil or nifedepine, whereas the PTX-induc Na influx was not affected by tetrodotoxin. 

Figure 1.4 Ionic basis for excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs). Resting membrane potential ( — 70 mV) is maintained by Na+ influx and K+ efflux. Varying degrees of depolarisation, shown by different sized EPSPs (a and b), are caused by increasing influx of Na. When the membrane potential moves towards threshold potential (60-65 mV) an action potential is initiated (c). The IPSPs (a b ) are produced by an influx of Cl. Coincidence of an EPSP (b) and IPSP (a ) reduces the size of the EPSP (d)...

Phase 0 Rapid depolarization occurs after threshold potential is reached owing to fast Na+ influx. The gradient of this line should be almost vertical as shown. 

Mechanism-specific adverse effects. Since local anesthetics block Na+ influx not only in sensory nerves but also in other excitable tissues, they are applied locally and measures are taken (p. 206) to impede their distribution into the body. Too rapid entry into the... 

Ach + receptor Na influx action potential increased free Ca contraction... 

The potential change depends on the nature of the ions crossing the membrane. If there is a Na influx, the membrane potential decreases and there is a depolarization. The membrane often gains a positive value by this process. In contrast, a efflux or a Cl" influx leads to hyperpolarization. The membrane potential becomes more negative than the resting potential. 

G protein-mediated responses to drugs and hormonal agonists often attenuate with time (Figure 2-12, top). After reaching an initial high level, the response (eg, cellular cAMP accumulation, Na+ influx, contractility, etc) diminishes over seconds or minutes, even in the continued presence of the agonist. This "desensitization" is often rapidly reversible a second exposure to agonist, if provided a few minutes after termination of the first exposure, results in a response similar to the initial response. 

Amiloride and triamterene are direct inhibitors of Na+ influx in the CCT (cortical collecting tubule). Triamterene is metabolized in the liver, but renal excretion is a major route of elimination for the active form and the metabolites. Because triamterene is extensively metabolized, it has a shorter half-life and must be given more frequently than amiloride (which is not metabolized). 

Ion channel modulation represents another approach to positive inotropy [13]. Sodium channel modulators increase Na+ influx and prolong the plateau phase of the action potential sodium/calcium exchange then leads to an increase in the level of calcium available to the contractile elements, thus increasing the force of cardiac contraction [13,14]. Synthetic compounds such as DPI 201-106 and BDF 9148 (Figure 1) increase the mean open time of the sodium channel by inhibiting channel inactivation [15]. Importantly, BDF 9148 remains an effective positive inotropic compound even in severely failing human myocardium [16] and in rat models of cardiovascular disease [17]. Modulators of calcium and potassium channel activities also function as positive inotropes [13], but in the remainder of this article we shall focus on sodium channel modulators. 

The voltage-gated Na+ and K+ channels of neuronal membranes carry the action potential along the axon as a wave of depolarization (Na+ influx) followed by repolarization (K+ efflux). 

Active transport of a solute against a concentration gradient also can be driven by a flow of an ion down its concentration gradient. Table 17.6 lists some of the active-transport systems that operate in this way. In some cases, the ion moves across the membrane in the opposite direction to the primary substrate (antiport) in others, the two species move in the same direction (symport). Many eukaryotic cells take up neutral amino acids by coupling this uptake to the inward movement of Na+ (see fig. 17.26c). As we discussed previously, Na+ influx is downhill thermodynamically because the Na+-K+ pump keeps the intracellular concentration of Na+ lower than the extracellular concentration and sets up a favorable electric potential difference across the membrane. Another example is the /3-galactosidc transport system of E. coli, which couples uptake of lactose to the inward flow of protons (see fig. 17.26Proton influx is downhill because electron-transfer reactions (or,... 

The situation for Na+ is quite different because both the concentration gradient and At// favor Na+ influx. The intracellular Na+ concentration in a mammalian neuron is about 15 mM, and the extracellular concentration is about 150 mM. Combining the concentration and electrical terms in this case gives... 

Experiments in which the salts in the extracellular and intracellular solutions were varied showed that the initial, rapid rise of At/r to a positive value results from a transient increase in the conductivity of the plasma membrane to Na+. The increased conductivity allows Na+ to flow rapidly into the cell, down its gradients of both concentration and electric potential (see equation (3)). However, Na+ influx shuts off abruptly in less than 1 ms, when the conductivity decreases again. As the conductivity to Na+ drops, the conductivity to K+ increases, and K+ begins to flow rapidly out of the cell. K+ efflux is favored, not only by the high ratio of the intracellular to extracellular K+ concentrations, but now also by Atp, which at this time is opposite in sign to the... 

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