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Membrane Potential, Ion Channels and Pumps

Membrane Potential, Ion Channels and Pumps
The cell membrane is a lipid bilayer with an intrinsically low permeability to charged ions. However, a variety of structures span the membrane through which ions can enter or leave the cell. These include ion channels through which ions passively diffuse and ion pumps which actively transport ions across the membrane. Pumps regulate ionic gradients, and channels determine membrane potential and underlie action potentials.

Resting membrane potential (Figure 10a)
The resting membrane is more permeable to K+ and Cl− than other ions, and is therefore semipermeable. The cell contains negatively charged molecules (e.g. proteins) which cannot cross the mem­ brane. This fixed negative charge attracts K+ but repels Cl−, leading to accumulation of K+ within the cell and loss of Cl. However, the consequent increase in K+ concentration gradient drives K+ back out of the cell. An equilibrium is reached when the electrical forces exactly balance those due to concentration differences (Gibbs–Donnan equilibrium); the net force or electrochemical gradient for K+ is then zero. The opposing effect of the concentration gradient means fewer K+ ions move into the cell than are required by the fixed negative charges. The inside of the cell is therefore negatively charged compared to the outside (charge separation), and a potential develops across the membrane. Only a small charge separation (e.g. 1 in 100 000 K+ ions) is required to cause a potential of 100 mV. If the membrane was only permeable to K+ and no other cations, the potential at equilibrium (K+ equilibrium potential, EK) would be defined by the K+ concentration gradient, and calculated from the Nernst equation. As cardiac muscle intra­ cellular [K+] is 120 mmol/L and extracellular [K+] 4 mmol/L EK = 90 mV (Figure 10a).
In real membranes K+ permeability (PK) at rest is indeed greater than for other ions, so the resting membrane potential (RMP) is close to EK (85 mV). RMP does not equal EK because there is some permeability to other ions; most notably Na+ permeability (PNa) is 1% of PK. The Na+ concentration gradient is also opposite to that for K+ (intracellular [Na+] 10 mmol/L, extracellular 140 mmol/L), because the Na+ pump (see below) actively removes Na+ from the cell. As a result, the theoretical equilibrium potential for Na+ (ENa) is +65 mV, far from the actual RMP. Both concentration and electrical gradients are therefore in the same direction, and this inward electrochemical gradient drives Na+ into the cell. As PNa at rest is relatively low, the amount of Na+ leaking into the cell is small, but is still sufficient to cause an inward current that slightly depolarizes the membrane. RMP is thus less negative than EK. RMP can be calculated using the Goldman equation, a derivation of the Nernst equation taking into account other ions and their permeabilities.
A consequence of the above is that if PNa was increased to more than PK, then the membrane potential would shift towards ENa. This is exactly what happens during an action potential, when Na+ channels open so that PNa becomes 10­fold greater than PK, and the membrane depolarizes (see Chapter 11). An equivalent situa­ tion arises for Ca2+, as intracellular [Ca2+] is 100 nmol/L at rest, much smaller than the extracellular [Ca2+] of 1 mmol/L.
Ion channels and gating (Figure 10b)
Channels differ in ion selectivity and activation mechanisms. They are either open or closed; transition between these states is called gating. When channels open ions move passively down their electrochemical gradient. As ions are charged, this causes an electrical current (ionic current); positive ions entering the cell cause inward currents and depolarization. Phosphorylation of channel proteins– by cAMP for example – can modify function, for example Ca2+ channels (see Chapter 11). There are several types of gating; two are described.

Voltage-gated channels (VGCs) are regulated by membrane potential. Some (e.g. certain K+ channels) simply switch between open and shut states according to the potential across them (Figure 10b). Others, such as the fast inward Na+ channel responsible for the upstroke of the action potential in nerves, skeletal and cardiac muscle (Figure 10b; see Chapter 11), have three states: open, shut and inactive. When a cell depolarizes sufficiently to activate these Na+ channels (i.e. reaches their threshold potential), they open and the cell depolarizes towards ENa. After a short period (<ms) the channels spontaneously inactivate, as though another gate had closed. Inactivated channels can only be reactivated once the mem­ brane potential becomes negative again. This is essential for generation of action potentials (see Chapter 11).

Membrane Potential, Ion Channels And Pumps, Resting membrane potential, Ion channels and gating, Voltage-gated channels, Ion pumps and membrane potential

Receptor-gated channels (RGCs; important in smooth muscle, see Chapter 15) are commonly non-selective cation channels (NSCCs; permeable to Na+ and Ca2+). They open when a hormone or neurotransmitter (e.g. noradrenaline) binds to a receptor and initiates production of a second messenger, such as diacylglycerol (DAG, Figure 10b).

Ion pumps and exchangers (Figure 10c)
Ion pumps use energy to transfer ions against their electrochemical gradient. Primary active transport consumes ATP for energy, the prime example being the Na+ pump (Na+–K+­ATPase), which pumps three Na+ out of the cell in exchange for two K+. Another is the Ca2+­ATPase that pumps Ca2+ into intracellular stores (see Chapters 12 and 15). Secondary active transport uses the Na+ electrochemical gradient generated by the Na+ pump to drive the transfer of other ions or molecules across the membrane. An example is the Na+–Ca2+ exchanger, which exchanges three Na+ ions for a Ca2+ ion (see Chapters 11 and 12). Na+ pump inhibitors (e.g. digoxin) reduce the Na+ gradient, and thus indirectly inhibit secondary transport. Pumps are regulated by ion concentrations, and modulated by second messengers.

Ion pumps and membrane potential
The Na+ pump and Na+–Ca2+ exchanger are electrogenic as unequal amounts of charge are transported, and thus a small ionic current is generated. They can therefore both affect, and be affected by, membrane potential. An example is Na+–Ca2+ exchange during the le action potential (see Chapters 11 and 12).