Simulation of the electrical activity of an excitable membrane with an electronic analog (author's transl)

1. The sodium and potassium conductances of the HODGKIN-HUXLEY model are simulated by a field effect transistor with a series resistor. This arrangement leads to a simple analog model of the excitable membrane (fig. 1 and 2). 2. Normally, the model is silent (fig. 3), but it becomes automatic (fig. 4) when the decay time (de-activation) of the potassium conductance is at least twice the recovery from inactivation time of the sodium conductance (taud greater than 2 tauri). 3. The effects of changes in sodium (fig. 5 and 6) and potassium (fig. 7, 8 and 9) concentration gradients upon the membrane potential and the ionic currents are easily studied when the model is silent or automatic. 4. When automatic, an increase in the potassium concentration gradient induces a lengthening of the period and ultimately, when the gradient is very high, spontaneous activity is blocked (fig. 9). On the other hand, increases of sodium gradient over 30% of normal value do not modify the period (fig 6). 5. The potassium concentration gradient modifies the excitability solely through membrane polarization (fig. 8), while sodium concentration has no effect on it (fig. 5). 6. Results with the model strengthen the hypothesis that tetraethylammonium (TEA) acts on both the maximum potassium conductance (gK) and the mechanism of sodium conductance inactivation (Tauh) to lengthen the action potential as observed on the Ranvier node (fig. 10). Effects of TEA on potassium conductance activation are also discussed. 7. Because of its simplicity and accuracy, this model lends itself easily to many other simulations.     

Potassium and sodium ions in the glycerinated skeletal muscle. Distribution changes induced by adenosine triphosphate and nondissociable anesthetic substances.

Investigation of the ionic behavior of glycerinated muscle fibers showed that the residual structures of this biologic cellular material, lacking functional membranes, are able to discriminate between alkaline ions. The characteristics of the ionic selectivity of the glycerinated fibers change with their functional state and with the presence in the medium of certain nonionic substances. Among the more important features of ionic distribution between the membrane-free fibers and the medium are the following: (1) There is evident adsorption of potassium on the fibers, in the absence of ATP. (2) This adsorption increases in contraction and decreases in relaxation. (3) At high ionic concentrations, in contrast to what occurs at low potassium concentrations, the glycerinated muscle prefers sodium to potassium, but even under these conditions both ions are accumulated in the fibers to far greater levels than in the medium. This strongly suggests a Donnan ionic equilibrium developing parallel to the adsorption process. (4) Nonionic substances of the general anesthetic group markedly alter the ionic selectivity of the glycerinated fibers, probably by their action on the water's physical state. A mechanism is proposed for the observed ionic adsorption specific of the muscle-a mechanism in which actin-myosin coupling plays the cardinal adsorption role. In the general interpretation of the data a synthetic concept is advanced according to which an entire set of processes and factors concurs with the distribution of ions between the muscle and the medium.     

Bupivacaine is an effective potassium channel blocker in heart

The local anesthetic agent bupivacaine increases action potential duration in isolated frog atrial myocytes, and blocks two potassium conductances, IK and IK1. The effective concentrations, particularly for IK, are similar to those which depress the sodium conductance. Potassium channel block may thus contribute to bupivacaine's reported cardiotoxicity.     

Effects of proteolytic enzymes on ionic conductances of squid axon membranes.

The effects of proteolytic enzymes on ionic conductances of squid axon membranes have been studied by means of the voltage clamp technique. When perfused internally alpha-chymotrypsin (1 mg/ml) increased and prolonged the depolarizing after-potential. Sodium inactivation was partially inhibited causing a prolonged sodium current, and peak sodium and steady-state potassium currents were suppressed. The time for sodium current to reach its peak was not affected. Leakage conductance increased later. On the other hand, carboxypeptidases A and B, both at 1mg/ml, suppressed the sodium and potassium conductance increases with little or no change in sodium inactivation. The mechanism that controls sodium inactivation appears to be associated with the structure of membrane proteins which is modified by alpha-chymotrypsin but not by carboxypeptidases and is located in a position accessible to alpha-chymotrypsin only from inside the membrane.     

Interactions of aminopyridines with potassium channels of squid axon membranes.

The effects of aminopyridines on ionic conductances of the squid giant axon membrane were examined using voltage clamp and internal perfusion techniques. 4-Aminopyridine (4-AP) reduced potassium currents, but had no effect upon transient sodium currents. The block of potassium channels by 4-AP was substantially less with (a) strong depolarization to positive membrane potentials, (b) increasing the duration of a given depolarizing step, and (c) increasing the frequency of step depolarizations. Experiments with high external potassium concentrations revealed that the effect of 4-AP was independent of the direction of potassium ion movement. Both 3- and 2-aminopyridine were indistinguishable from 4-AP except in potency. It is concluded that aminopyrimidines may be used as tools to block the potassium conductance in excitable membranes, but only within certain specific voltage and frequency limits.     

Electrolyte transport across rabbit late proximal colon in vitro

The second part of rabbit proximal colon was investigated in vitro under short circuit conditions. Unidirectional sodium and chloride fluxes were measured during the soft faeces period and during the hard faeces period. Rabbit late proximal colon has a potential difference (psi mS) of 4 mV, a tissue conductance (GT) of 10-11 mS/cm2 and a short circuit current (Isc) of 1.5 mueq/cm2 X hr. Under control conditions sodium (2.65 mueq/cm2 X hr) and chloride (0.67 mueq/cm2 X hr) are absorbed. Ouabain abolished psi ms,Isc and the net sodium flux totally, whereas 0.1 mM amiloride only slightly decreased the net sodium flux. No differences in electrical properties and Na,Cl-fluxes were found between the faeces periods. Removal of sodium abolished psi ms and Isc totally, and a high potassium solution depolarized the preparation (psi ms = 0). A linear current-voltage relation characterizes the tissue as an ohmic resistor between -40 and +50 mV, and reveals a slope conductance of 14 mS/cm2 under KCl conditions. We conclude that the transport functions under in vitro conditions differ markedly from the in vivo situation, and that the diurnal differences of electrolyte transport in vivo occur mainly by the involvement of ionic gradients.     

The electrical potential profile of gallbladder epithelium.

In this study the relative ionic permeabilities of the cell membranes of Necturus gallbladder epithelium have been determined by means of simultaneous measurement of transmural and transmucosal membrane potential differences (PD) and by ionic substitution experiments with sodium, potassium and chloride ions. It is shown that the mucosal membrane is permeable to sodium and to potassium ions. The baso-lateral membrane PD is only sensitive to potassium ions. In both membranes chloride conductance is negligible or absent. The ratio of the resistances of the mucosal and baso-lateral membranes, RM/RS, increases upon reducing the sodium concentration in the mucosal solution. The same ratio decreases when sodium is replaced by potassium which implies a greater potassium than sodium conductance in the mucosal membrane. The relative permeability of the shunt for potassium, sodium and chloride ions is: PK/PNa/PCl=1.81:1.00:0.32. From the results obtained in this study a value for the PK/PNa ratio of the mucosal membrane could be evaluated. This ratio is 2.7. From the same data the magnitude of the electromotive forces generated across the cell membranes could be calculated. The EMF's are -15mV across the mucosal membrane and -81mV across the baso-lateral one. Due to the presence of the low resistance shunt the transmucosal membrane PD is -53.2mV (cell inside negative) and the transmural PD is +2.6mV (serosal side positive). The change in potential profile brought about by the low resistance shunt favors passive entry of Na ions into the cell across the mucosal membrane. Calculations show that this passive Na influx is maximally 64% of the net Na flux estimated from fluid transport measurements. The C-1 conductive of the baso-lateral membrane is too small to allow electrogenic coupling of C1 with Na transport across this membrane. Experiments with rabbit gallbladder epithelium indicate that the membrane properties in this tissue are qualitatively similar to those of Necturus gallbladder epithelium.     

On the voltage-dependent action of tetrodotoxin.

The use of the maximum rate-of-rise of the action potential (Vmax) as a measure of the sodium conductance in excitable membranes is invalid. In the case of membrane action potentials, Vmax depends on the total ionic current across the membrane; drugs or conditions that alter the potassium or leak conductances will also affect Vmax. Likewise, long-term depolarization of the membrane lessens the fraction of total ionic current that passes through the sodium channels by increasing potassium conductance and inactivating the sodium conductance, and thereby reduces the effect of Vmax of drugs that specifically block sodium channels. The resultant artifact, an apparent voltage-dependent potency of such drugs, is theoretically simulated for the effects of tetrodotoxin on the Hodgkin-Huxley squid axon.     

The development of voltage-dependent ionic conductances in murine spinal cord neurones in culture

The development of voltage-dependent ionic conductances of foetal mouse spinal cord neurones was examined using the whole-cell patch-clamp technique on neurones cultured from embryos aged 10-12 days (E10-E12) which were studied between the first day in vitro (V1) to V10. A delayed rectifier potassium conductance (Ik) and a leak conductance were observed in neurones of E10, V1, E11, V1, and E12, V1 as well as in neurones cultured for longer periods. A rapidly activating and inactivating potassium conductance (IA) was seen in neurones from E11. V2 and E12, V1 and at longer times in vitro. A tetrodotoxin (TTX) sensitive sodium-dependent inward current was observed in neurones of E11 and E12 from V1 onwards. Calcium-dependent conductances were not detectable in these neurones unless the external calcium concentration was raised 10-to 20-fold and potassium conductances were blocked. Under these conditions calcium currents could be observed as early as E11. V3 and E12, V2 and at subsequent times in vitro. The pattern of development of voltage-dependent ionic conductances in murine spinal neurones is such that initially leak and potassium currents are present followed by sodium current and subsequently calcium current.     

Multiple-state model of ionic channel in reproducing the time course of electrophysiological events.

BACKGROUND: The predictions of the Hodgkin-Huxley model do not accurately fit all the measurements of voltage-clamp currents, gating charge and single-channel currents. There are many quantitative differences between the predicted and measured characteristics of the sodium and potassium channels. For example, the two-state gate model has exponential onset kinetics, whereas the sodium and potassium conductances show S-shaped activation and the sodium conductance shows an exponential inactivation. In this paper we shall examine a more general channel model that can more faithfully represent the measured properties of ionic channels in the membrane of the excitable cell. METHODS: The model is based on the generalisation of the notion of a channel with a discrete set of states. Each state has state attributes such as the state conductance, state ionic current and state gating charge. These variables can have quite different waveforms in time, in contrast with a two-state gate channel model, in which all have the same waveforms. RESULTS: The kinetics of all variables are equivalent: gating and ionic currents give equivalent information about channel kinetics; both the equilibrium values of the current and the time constants are functions of membrane potential. The results are in almost perfect concordance with the experimental data regarding the characteristics of nerve impulse. CONCLUSIONS: The expected values of the gating charge and the ionic conductance are weighted sums of the state occupancy probabilities, but the weights differ: for the expected value of the gating charge the weights are the state gating charges and for the expected value of the ionic conductance the weights are the state conductances. Since these weights are different, the expected values of the gating charge and the ionic conductance will differ.     

Ionic permeability of K, Na, and Cl in crayfish nerve. Regulation by membrane fixed charges and pH.

Teorell's fixed charge theory for membrane ion permeability was utilized to calculate specific ionic permeabilities from measurements of membrane potential, conductance, and specific ionic transference numbers. The results were compared with the passive ionic conductances calculated from the branched equivalent circuit membrane model of Hodgkin Huxley. Ionic permeabilities for potassium, sodium, and chloride of crayfish (Procambarus clarkii) medial giant axons were examined over an external pH range from 3.8 to 11.4. Action potentials were obtained over this pH range. Failures occurred below pH 3.8 during protonation of membrane phospholipid phosphate and carboxyl, and above pH 11.4 from calcium precipitation. In general, chloride permeability increases with membrane protonation, while cation permeability decreases. At pH 7.0, PK = 1.33 X 10(-5), PCl = 1.49 X 10(-6), PNa = 1.92 X 10(-8) cm/s. PK: PCl: PNa = 693:78:1. PCl is zero above pH 10.6 and is opened predominately by protonation of epsilon-amino, and partially by tyrosine and sulfhydryl groups from pH 10.6 to 9. PK is activated in part by ionization of phospholipid phosphate and carboxyl around pH 4, then further by imidazole from pH 5 to 7, and then predominately from pH 7 to 9 by most probably phosphatidic acid. PNa permeability parallels that of potassium from pH 5 to 9.4. Below pH 5 and above pH 9.4, PNa increases while PK decreases. Evidence was obtained that these ions possibly share common passive permeable channels. The data best support the theory of Teorell, that membrane fixed charges regulate permiability and that essentially every membrane ionizable group appears involved in various amounts in ionic permeability control.     

Nalorphine: actions at an opiate receptor on frog skeletal muscle fibers

Intracellular microelectrode studies were conducted to investigate the actions of the partial agonist-antagonist nalorphine at an opiate receptor on functional frog skeletal muscle fiber membranes. In high bath concentrations (greater than or equal to 10(-4) M), nalorphine alone produces agonist actions similar to the "full" opiate agonists. These actions were (i) to depress both the sodium and potassium (gNa and gK) conductance increases due to electrical stimulation by a nonspecific local anestheticlike mechanism and (ii) to depress gNa by a specific opiate receptor mediated mechanism. In a much lower bath concentration (1 X 10(-8) M) nalorphine acts to antagonize the specific opiate receptor mediated depression of gNa produced by the "full" agonist meperidine. Thus in this preparation nalorphine, "the partial antagonist," has the same actions as naloxone, which is often considered to be a full antagonist. The quantitative differences observed in the effects of these two opiate antagonists are discussed.     

The ionic mechanism associated with the action of putative transmitters on identified neurons of the snail, Helix aspersa

Intracellular recordings were made from identified neurons in the suboesophageal ganglionic mass of the snail, Helix aspersa. The ionic mechanisms associated with acetylcholine excitation and inhibition, dopamine excitation and inhibition, gamma-aminobutyric acid (GABA) excitation and inhibition and serotonin excitation were investigated. Acetylcholine excitation was found to involve an initial increase in sodium conductance while acetylcholine inhibition was a pure chloride event which reversed at membrane potentials more negative than the chloride equilibrium potential. Dopamine excitation appeared to involve only an increase in sodium conductance while serotonin excitation involved an increase in conductance to both sodium and calcium ions. Dopamine inhibition was associated with an increase in potassium conductance but failed to reverse at membrane potentials more negative than the potassium equilibrium potential. GABA excitation involved conductance increases to both sodium and chloride ions while GABA inhibition was a pure chloride event. An attempt was made to estimate the degree of co-operativity of the putative transmitters with their receptors using log-log and Hill plots. The slopes of the line for the log-log plots for acetylcholine excitation and inhibition were 0.88 and 1.1, respectively, suggesting the interaction of one molecule of acetylcholine with the receptor. The slope of the log-log plot for dopamine inhibition was 0.46 while that for serotonin excitation was 0.75. The Hill plots for GABA excitation and inhibition were 1.64 and 1.42, respectively, suggesting that two molecules of GABA are required for receptor activation.     

Effect of the general anesthetic ketamine on the potassium permeability of plasma membranes of brain synaptosomes

General anesthetic ketamine (1 mM) decreases relative sodium permeability (PNa+/PK+) of synaptosomes measured by transmembrane potential--external potassium concentration curves. Since tetrodotoxin (10(-7) M) does not affect the value PNa+/PK+ it is concluded that potassium permeability of the membrane increases in the presence of ketamine.     

Effect of service number on estrus duration in dairy goats

The object of this research was to study the effect of sterile service number on estrus duration in dairy goats. Twenty-four Nubian goats (20 nulliparous and 4 multiparous) were randomly assigned to 1 of 4 treatment groups (n = 6 animals per group). The following Groups were formed: no service (GS-0); 1 service (GS-1); 2 services (GS-2); 3 services (GS-3). Estrus was synchronized by using fluorogestone acetate intravaginal pessaries (40 mg) over a 12-d period plus 400 IU im pregnant mare serum gonadotropin (PMSG) at pessary removal. Estrus was detected by using a vasectomized buck at 6-h intervals over 5 d after pessary removal (at 0600, 1200, 1800 and 2400 h). In the GS-0 group the teaser was outfitted with an apron and was permitted to mount. In the GS-1, GS-2 and GS-3 groups, the teaser was permitted to mount and service 1, 2 and 3 times, respectively, within the first 12 h after initiation of estrus. The duration of estrus for the 4 groups (GS-0, GS-1, GS-2 and GS-3) was (mean +/- SD) 41.0 +/- 5.9, 24.0 +/- 5.4, 22.0 +/- 4.9 and 22.0 +/- 7.2 h, respectively. These results show differences between the serviced groups and the nonserviced group (P<0.01), but they fail to show differences among the serviced groups (P>0.05). It is concluded that sterile service shortens estrus duration and that service number (1, 2 or 3) does not affect estrus duration.     

Effects of the dipolar form of phloretin on potassium conductance in squid giant axons.

The effects of phloretin on membrane ionic conductances have been studied in the giant axon of the squid, Loligo pealei. Phloretin reversibly suppresses the potassium and sodium conductances and modifies their dependence on membrane potential (Em). Its effects on the potassium conductance (GK) are much greater than on the sodium conductance; no effects on sodium inactivation are observed. Internal perfusion of phloretin produces both greater shifts in GK(Em) and greater reductions maximum GK than does external perfusion; the effect of simultaneous internal and external perfusion is little greater than that of internal perfusion alone. Lowering the internal pH, which favors the presence of the neutral species of weakly acidic phloretin (pKa 7.4), potentiates the actions of internally perfused phloretin. Other organic cations with dipole moments similar to phloretin's have little effect on either potassium or sodium conductances in squid axons. These results can be explained by either of two mechanisms; on postulates a phloretin "receptor" near the voltage sensor component of the potassium channel which is accessible to drug molecules applied at either the outer or inner membrane surface and is much more sensitive to the neutral than the negatively charged form of the drug. The other mechanism proposes that neutral phloretin molecules are dispersed in an ordered array in the membrane interior, producing a diffuse dipole field which modifies potassium channel gating. Different experimental results support these two mechanisms, and neither hypothesis can be disproven.     

Ionic currents in two strains of rat anterior pituitary tumor cells

The ionic conductance mechanisms underlying action potential behavior in GH3 and GH4/C1 rat pituitary tumor cell lines were identified and characterized using a patch electrode voltage-clamp technique. Voltage-dependent sodium, calcium, and potassium currents and calcium-activated potassium currents were present in the GH3 cells. GH4/C1 cells possess much less sodium current, less voltage-dependent potassium current, and comparable amounts of calcium current. Voltage-dependent inward sodium current activated and inactivated rapidly and was blocked by tetrodotoxin. A slower-activating voltage-dependent inward calcium current was blocked by cobalt, manganese, nickel, zinc, or cadmium. Barium was substituted for calcium as the inward current carrier. Calcium tail currents decay with two exponential components. The rate constant for the slower component is voltage dependent, while the faster rate constant is independent of voltage. An analysis of tail current envelopes under conditions of controlled ionic gradients suggests that much of the apparent decline of calcium currents arises from an opposing outward current of low cationic selectivity. Voltage-dependent outward potassium current activated rapidly and inactivated slowly. A second outward current, the calcium-activated potassium current, activated slowly and did not appear to reach steady state with 185-ms voltage pulses. This slowly activating outward current is sensitive to external cobalt and cadmium and to the internal concentration of calcium. Tetraethylammonium and 4-aminopyridine block the majority of these outward currents. Our studies reveal a variety of macroscopic ionic currents that could play a role in the initiation and short-term maintenance of hormone secretion, but suggest that sodium channels probably do not make a major contribution.     

Effects of physostigmine on the voltage dependent ionic conductances of skeletal muscle fibres

The voltage dependent ionic conductances were studied by analysing the phase plane trajectories of action potentials evoked by electrical stimulation of the sartorius muscles of the frog (Rana esculenta). The delayed outward potassium current was measured also under voltage clamp conditions on muscle fibres of either the frog (Rana esculenta) or Xenopus laevis. On analysing the effect of physostigmine decreasing the peak amplitude, the rate of both the rising and falling phases of the action potentials, it was revealed that the alkaloid at a concentration of 1 mmol/l reduced significantly both the delayed potassium conductance and the outward ionic current values during the action potentials. The inhibition of sodium conductance and inward ionic current was less expressed. The maximum value of delayed potassium conductance measured under voltage clamp conditions was decreased by 1 mmol/l physostigmine. The time constant determined from the development of delayed potassium conductance was increased at a given membrane potential. The voltage vs. n relationship describing the membrane potential dependence of the delayed rectifier was not influenced by physostigmine. It has been concluded that physostigmine changes the time course of the action potentials by decreasing the value of both voltage dependent ionic conductances and by slowing down their kinetics. It is discussed that results obtained from the phase plane analysis of complex pharmacological effects can only be accepted with some restrictions.     

Acetylcholine receptor in planar lipid bilayers. Characterization of the channel properties of the purified nicotinic acetylcholine receptor from Torpedo californica reconstituted in planar lipid bilayers

The properties of the channel of the purified acetylcholine receptor (AChR) were investigated after reconstitution in planar lipid bilayers. The time course of the agonist-induced conductance exhibits a transient peak that relaxes to a steady state value. The macroscopic steady state membrane conductance increases with agonist concentration, reaching saturation at 10(-5) M for carbamylcholine (CCh). The agonist-induced membrane conductance was inhibited by d-tubocurarine (50% inhibition, IC50, at approximately 10(-6) M) and hexamethonium (IC50 approximately 10(-5) M). The single channel conductance, gamma, is ohmic and independent of the agonist. At 0.3 M monovalent salt concentrations, gamma = 28 pS for Na+, 30 pS for Rb+, 38 pS for Cs+, and 50 pS for NH+4. The distribution of channel open times was fit by a sum of two exponentials, reflecting the existence of two distinct open states. tau o1 and tau o2, the fast and slow components of the distribution of open times, are independent of the agonist concentration: for CCh this was verified in the range of 10(-6) M less than C less than 10(-3)M. tau 01 and tau o2 are approximately three times longer for suberyldicholine ( SubCh ) than for CCh. tau o1 and tau o2 are moderately voltage dependent, increasing as the applied voltage in the compartment containing agonist is made more positive with respect to the other. At desensitizing concentrations of agonist, the AChR channel openings occurred in a characteristic pattern of sudden paroxysms of channel activity followed by quiescent periods. A local anesthetic derivative of lidocaine ( QX -222) reduced both tau o1 and tau o2. This effect was dependent on both the concentration of QX -222 and the applied voltage. Thus, the AChR purified from Torpedo electric organ and reconstituted in planar lipid bilayers exhibits ion conduction and kinetic and pharmacological properties similar to AChR in intact muscle postsynaptic membranes.     

Ionic permeability of K, Na, and Cl in potassium-depolarized nerve. Dependency on pH, cooperative effects, and action of tetrodotoxin.

The passive ionic membrane conductances (gj) and permeabilities (Pj) of K, Na, and Cl of crayfish (Procambarus clarkii) medial giant axons were determined in the potassium-depolarized axon and compared with that of the resting axon. Passive ionic conductances and permeabilities were found to be potassium dependent with a major conductance transition occurring around an external K concentration of 12-15 mM (Vm = -60 to -65 mV). The results showed that K, Na, and Cl conductances increased by 6.2, 6.9, and 27-fold, respectively, when external K was elevated from 5.4 to 40 mM. Permeability measurements indicated that K changed minimally with K depolarization while Na and Cl underwent an order increase in permeability. In the resting axon (K0 = 5.4 mM, pH = 7.0) PK = 1.33 X 10(-5), PCl = 1.99 X 10(-6), PNa = 1.92 X 10(-8) while in elevated potassium (K0 = 40 mM, pH 7.0), PK = 1.9 X 10(-5), PCl = 1.2 X 10(-5), and PNa = 2.7 X 10(-7) cm/s. When membrane potential is reduced to 40 mV by changes in internal ions, the conductance changes are initially small. This suggests that resting channel conductances depend also on ion environments seen by each membrane surface in addition to membrane potential. In elevated potassium, K, Na, and Cl conductances and permeabilities were measured from pH 3.8 to 11 in 0.2 pH increments. Here a cooperative transition in membrane conductance or permeability occurs when pH is altered through the imidazole pK (approximately pH 6.3) region. This cooperative conductance transition involves changes in Na and Cl but not K permeabilities. A Hill coefficient n of near 4 was found for the cooperative conductance transition of both the Na and Cl ionic channel which could be interpreted as resulting from 4 protein molecules forming each of the Na and Cl ionic channels. Tetrodotoxin reduces the Hill coefficient n to near 2 for the Na channel but does not affect the Cl channel. In the resting or depolarized axon, crosslinking membrane amino groups with DIDS reduces Cl and Na permeability. Following potassium depolarization, buried amino groups appear to be uncovered. The data here suggest that potassium depolarization produces a membrane conformation change in these ionic permeability regulatory components. A model is proposed where membrane protein, which forms the membrane ionic channels, is oriented with an accessible amino terminal group on the axon exterior. In this model the ionizable groups on protein and phospholipid have varied associations with the different ionic channel access sites for K, Na, and Cl, and these groups exert considerable control over ion permeation through their surface potentials.