51
4
forms the conductance pore and the selectivity filter. The cytoplasmic loops have binding
sites for downstream effectors. For example, L-type channels on skeletal muscle cells interact directly with the ryanodine receptors RYR1 through a specific amino acid motif in
their cytoplasmic loops between subdomains two and three of the α-subunit. In this way,
a depolarization signal at the muscle cell membrane at the neuromuscular junction triggers Ca 2+ -release from the sarcoplasmic reticulum for muscle contraction. Moreover, neuronal N-type or P/Q-type channels interact directly with SNARE proteins of the
exocytosis complex at presynaptic nerve endings. This allows fast relay of action potentials
to vesicle fusion and neurotransmitter release (see . Fig. 4.3c).
The activity of VOC channels can furthermore be regulated by many signalling molecules, including PKA, Gβ/γ-subunits and Ca 2+ -ions (Berridge 2012).
4.3.4 Neuromuscular Junction
Ca 2+ -entry channels on excitable cells are best known from their involvement in regulating muscle contraction and neurotransmitter release. As an example to illustrate the
physiological cooperation of different ion channels during synaptic transmission, the neuromuscular junction is described. At this synapse, motor neurons projecting from the
spinal cord make contact with muscle fibres to activate muscle contraction. For this
purpose, two Ca 2+ -channels co-operate in the muscle cell, ryanodine receptors (RYR) on
the membrane of the sarcoplasmic reticulum (the muscle cell ER) and L-type voltagegated Ca 2+ -channels on the plasma membrane of the muscle cell (see . Fig. 4.4).
The neurotransmitter conveying the action potential of the excited motor neuron to the
postsynaptic membrane of the muscle cell is acetylcholine. Acetylcholine “gates” the nicotinic acetylcholine receptor (NAchR), an ion channel on the muscle cell. Acetylcholine
binding leads to Na + and Ca 2+ -influx into the muscle cell, membrane depolarization and
opening of voltage-gated Na + -channels. This further depolarizes the membrane and eventually results in opening of high voltage-activated L-type Ca 2+ -channels on the plasma membrane of muscle fibres (L-VOCs). The L-type VOCs can be inhibited with dihydropyridine,
a synthetic Ca 2+ -channel blocker that is pharmacologically used to treat hypertension.
Ca 2+ is an essential component for muscle contraction. A muscle contracts when actin
fibres are moved by myosin, the actin motor protein. In the resting state, actin fibres in
skeletal and heart muscle cells are covered with tropomyosin, which is bound to the Ca 2+ -
binding protein troponin. In the Ca 2+ -free state, tropomyosin filaments therefore block
the myosin-binding sites on the actin filaments. When Ca 2+ -ions are released from the
sarcoplasmic reticulum, they bind to troponin allowing tropomyosin filaments to move
away from the myosin-binding sites. Myosin is now able to contact and move the actin
filaments and the muscle contracts. The responsible Ca 2+ -channels are Ca 2+ -gated
ryanodine (RYR) receptors on the SR membrane. They open in response to the Ca 2+ -
signal that is created after excitation of the muscle cell (see . Fig. 4.4).
RYR receptors have their name because they are sensitive to the plant alkaloid ryanodine, a poison and insecticide from Ryania speciosa, a South American member of the
Salicaceae family. They differ from the previously described plasma membrane voltagegated Ca 2+ -channels by their size and their five times higher ion conductance. They are
assembled from four monomers, each consisting of ca. 5000 amino acids. This size enables
visibility of these receptors in electron microscopy studies. Such images show RYR receptors as electron-dense protrusions in the junctions between transverse tubular invaginations of the plasma membrane and the sarcoplasmic reticulum. Several subtypes are
4.3 · Voltage-Gated Ion Channels
4
forms the conductance pore and the selectivity filter. The cytoplasmic loops have binding
sites for downstream effectors. For example, L-type channels on skeletal muscle cells interact directly with the ryanodine receptors RYR1 through a specific amino acid motif in
their cytoplasmic loops between subdomains two and three of the α-subunit. In this way,
a depolarization signal at the muscle cell membrane at the neuromuscular junction triggers Ca 2+ -release from the sarcoplasmic reticulum for muscle contraction. Moreover, neuronal N-type or P/Q-type channels interact directly with SNARE proteins of the
exocytosis complex at presynaptic nerve endings. This allows fast relay of action potentials
to vesicle fusion and neurotransmitter release (see . Fig. 4.3c).
The activity of VOC channels can furthermore be regulated by many signalling molecules, including PKA, Gβ/γ-subunits and Ca 2+ -ions (Berridge 2012).
4.3.4 Neuromuscular Junction
Ca 2+ -entry channels on excitable cells are best known from their involvement in regulating muscle contraction and neurotransmitter release. As an example to illustrate the
physiological cooperation of different ion channels during synaptic transmission, the neuromuscular junction is described. At this synapse, motor neurons projecting from the
spinal cord make contact with muscle fibres to activate muscle contraction. For this
purpose, two Ca 2+ -channels co-operate in the muscle cell, ryanodine receptors (RYR) on
the membrane of the sarcoplasmic reticulum (the muscle cell ER) and L-type voltagegated Ca 2+ -channels on the plasma membrane of the muscle cell (see . Fig. 4.4).
The neurotransmitter conveying the action potential of the excited motor neuron to the
postsynaptic membrane of the muscle cell is acetylcholine. Acetylcholine “gates” the nicotinic acetylcholine receptor (NAchR), an ion channel on the muscle cell. Acetylcholine
binding leads to Na + and Ca 2+ -influx into the muscle cell, membrane depolarization and
opening of voltage-gated Na + -channels. This further depolarizes the membrane and eventually results in opening of high voltage-activated L-type Ca 2+ -channels on the plasma membrane of muscle fibres (L-VOCs). The L-type VOCs can be inhibited with dihydropyridine,
a synthetic Ca 2+ -channel blocker that is pharmacologically used to treat hypertension.
Ca 2+ is an essential component for muscle contraction. A muscle contracts when actin
fibres are moved by myosin, the actin motor protein. In the resting state, actin fibres in
skeletal and heart muscle cells are covered with tropomyosin, which is bound to the Ca 2+ -
binding protein troponin. In the Ca 2+ -free state, tropomyosin filaments therefore block
the myosin-binding sites on the actin filaments. When Ca 2+ -ions are released from the
sarcoplasmic reticulum, they bind to troponin allowing tropomyosin filaments to move
away from the myosin-binding sites. Myosin is now able to contact and move the actin
filaments and the muscle contracts. The responsible Ca 2+ -channels are Ca 2+ -gated
ryanodine (RYR) receptors on the SR membrane. They open in response to the Ca 2+ -
signal that is created after excitation of the muscle cell (see . Fig. 4.4).
RYR receptors have their name because they are sensitive to the plant alkaloid ryanodine, a poison and insecticide from Ryania speciosa, a South American member of the
Salicaceae family. They differ from the previously described plasma membrane voltagegated Ca 2+ -channels by their size and their five times higher ion conductance. They are
assembled from four monomers, each consisting of ca. 5000 amino acids. This size enables
visibility of these receptors in electron microscopy studies. Such images show RYR receptors as electron-dense protrusions in the junctions between transverse tubular invaginations of the plasma membrane and the sarcoplasmic reticulum. Several subtypes are
4.3 · Voltage-Gated Ion Channels