47
4
reticulum. Here we find ATP-driven Ca 2+ -pumps, including the sarco−/endoplasmic
reticulum Ca 2+ -ATPase (SERCA) of muscle cells, which pump Ca 2+ -ions into the lumen
of the ER. Digitoxin, a glycoside from Digitalis purpurea blocks the 3Na + /2 K + ATPase in
heart muscle cells, which counts for the effects of this drug on heart function.
Ion channels, in contrast to ATP-driven ion pumps, allow passage of ions according to
their concentration gradient. This does not require energy. Some K + -channels are always, at
least partially, open, which induces an outward K + -current, leaving the inside of the membrane negatively charged in the resting state. On the other hand, Na + -channels are not constitutively open, making the membrane seemingly impermeable for these ions and allowing
a high extracellular Na + -concentration. This is important for the osmotic balance of the
cells. Moreover, opening of gated Na + -channels leads to influx of Na + -ions upon a stimulus,
making the membrane potential more positive. This is called depolarization. Vice versa,
opening of gated Cl − -channels allows influx of negatively charged ions (Cl − -concentration
is usually higher outside the cell) – resulting in a decrease of the membrane potential, which
is called hyperpolarization. Similarly, opening of K + -channels increases efflux of positive
ions and hyperpolarizes the membrane. An interesting class of K + -channels are G-protein
regulated inwardly rectifying channels (GIRK channels, (Luscher and Slesinger 2010)).
They open in response to Gβ/γ-subunits of activated trimeric G-proteins and, under certain
conditions, show higher inward current of K + -ions than outward current. This represents a
reversal of the expected K + -ion flow according to the physiological K + -ion concentrations
outside and inside the membrane. It is caused by intracellular Mg + -ions and polyamines,
which occlude the channel pore for outward K + -currents. This occurs at the equilibrium
membrane potential for K + -ions of −90 mV. At resting membrane potential, opening of
GIRKs increases K + -conductance leading to hyperpolarization. However, when the extracellular concentration of K + -ions reaches ca. 20 mM, inward current of K + -ions outweighs
outward current (Bichet et al. 2003; Isomoto et al. 1997).
4.3 Voltage-Gated Ion Channels
Voltage-gated ion channels (VOCs) are closed at resting membrane potential and open
when the membrane is depolarized. All voltage-gated ion channels have three important
structural components.
1. A transmembrane structure harbours a central pore for the ions to pass.
2. A voltage-sensing helix moves in response to changes in the membrane potential. It
is part of a larger voltage-sensing domain spanning the membrane four times.
3. A plug-like structure that closes the channel after ions have moved through.
4.3.1 Voltage-Gated K + -Channels
Voltage-gated K + -channels are composed of four channel forming α-subunits and accessory β-subunits, the latter not being involved in ion conductance. K + -channel α-subunits
constitute a protein family with 40 members grouped into 12 classes. They are named
K v α1-12 and produce channels with different properties. In Kvα 1-channels, four subunits
of 600–700 amino acids’ length, each spanning the membrane six times, make up the pore.
Within the same subfamilies, α-subunits can homo- or hetero-oligomerize, and therefore
the diversity of K v -channel oligomers that exist in cells is very high. Some family members
4.3 · Voltage-Gated Ion Channels
4
reticulum. Here we find ATP-driven Ca 2+ -pumps, including the sarco−/endoplasmic
reticulum Ca 2+ -ATPase (SERCA) of muscle cells, which pump Ca 2+ -ions into the lumen
of the ER. Digitoxin, a glycoside from Digitalis purpurea blocks the 3Na + /2 K + ATPase in
heart muscle cells, which counts for the effects of this drug on heart function.
Ion channels, in contrast to ATP-driven ion pumps, allow passage of ions according to
their concentration gradient. This does not require energy. Some K + -channels are always, at
least partially, open, which induces an outward K + -current, leaving the inside of the membrane negatively charged in the resting state. On the other hand, Na + -channels are not constitutively open, making the membrane seemingly impermeable for these ions and allowing
a high extracellular Na + -concentration. This is important for the osmotic balance of the
cells. Moreover, opening of gated Na + -channels leads to influx of Na + -ions upon a stimulus,
making the membrane potential more positive. This is called depolarization. Vice versa,
opening of gated Cl − -channels allows influx of negatively charged ions (Cl − -concentration
is usually higher outside the cell) – resulting in a decrease of the membrane potential, which
is called hyperpolarization. Similarly, opening of K + -channels increases efflux of positive
ions and hyperpolarizes the membrane. An interesting class of K + -channels are G-protein
regulated inwardly rectifying channels (GIRK channels, (Luscher and Slesinger 2010)).
They open in response to Gβ/γ-subunits of activated trimeric G-proteins and, under certain
conditions, show higher inward current of K + -ions than outward current. This represents a
reversal of the expected K + -ion flow according to the physiological K + -ion concentrations
outside and inside the membrane. It is caused by intracellular Mg + -ions and polyamines,
which occlude the channel pore for outward K + -currents. This occurs at the equilibrium
membrane potential for K + -ions of −90 mV. At resting membrane potential, opening of
GIRKs increases K + -conductance leading to hyperpolarization. However, when the extracellular concentration of K + -ions reaches ca. 20 mM, inward current of K + -ions outweighs
outward current (Bichet et al. 2003; Isomoto et al. 1997).
4.3 Voltage-Gated Ion Channels
Voltage-gated ion channels (VOCs) are closed at resting membrane potential and open
when the membrane is depolarized. All voltage-gated ion channels have three important
structural components.
1. A transmembrane structure harbours a central pore for the ions to pass.
2. A voltage-sensing helix moves in response to changes in the membrane potential. It
is part of a larger voltage-sensing domain spanning the membrane four times.
3. A plug-like structure that closes the channel after ions have moved through.
4.3.1 Voltage-Gated K + -Channels
Voltage-gated K + -channels are composed of four channel forming α-subunits and accessory β-subunits, the latter not being involved in ion conductance. K + -channel α-subunits
constitute a protein family with 40 members grouped into 12 classes. They are named
K v α1-12 and produce channels with different properties. In Kvα 1-channels, four subunits
of 600–700 amino acids’ length, each spanning the membrane six times, make up the pore.
Within the same subfamilies, α-subunits can homo- or hetero-oligomerize, and therefore
the diversity of K v -channel oligomers that exist in cells is very high. Some family members
4.3 · Voltage-Gated Ion Channels