46
4
evokes transcriptional, metabolic or behavioural responses in target cells. GPCRs activated by neuromodulators are often also found in presynaptic membranes (Civelli 2012).
Interestingly, transmitter molecules may act on LGICs and also on GPCRs as we will see
later, for instance, for GABA, glutamate, acetylcholine and serotonin.
Most neurotransmitters and neuromodulators are stored in vesicles at presynaptic
axon terminals. Many of these vesicles are already tethered to the membrane and ready to
be released. The amount of neurotransmitter available for binding to receptors on the
postsynaptic membrane depends on:
1. The frequency of arriving action potentials leading to their release.
2. The retrieval of the neurotransmitter back into the presynaptic neuron.
3. The inclusion of neurotransmitters into neuronal storage granules.
4. The degradation of the neurotransmitter within the synaptic cleft or in the cytoplasm
of the neuron.
Vesicle fusion and transmitter release occur after the action potential arrives. A voltagedependent Ca 2+ -channel (see later) opens, and Ca 2+ flows into the cytoplasm. Ca 2+ -ions
provide the trigger for the excitatory machinery to release the content of neurotransmitter
vesicles. Most neurotransmitters and neuromodulators will be retrieved after their release.
For this task, presynaptic membranes have specific transporters, e.g. the dopamine transporter DAT. Cytoplasmic neurotransmitters are transported into storage granules by specific symporters, e.g. the vesicular monoamine transporter VMAT. Degradation of
synaptic transmitters occurs through enzymes that are secreted into the synaptic cleft.
One example is the acetylcholine esterase, which cleaves the neurotransmitter acetylcholine into acetate and choline.
4.2 Membrane Potential and Electrochemical Gradient
The basis for the function of voltage-gated ion channels is the electrochemical gradient
across the plasma membrane. Such a gradient exists in all cells of the body, in muscle and
gland cells as well as in excitable cells, like nerve cells, where it is used for electrochemical
signalling, e.g. the generation of action potentials. The electrochemical gradient is due to
differences in the concentration of Na + , K + and Ca 2+ ions between the cytoplasm and the
extracellular space. These differences are maintained in all cells. They are generated by
ATP-dependent ion pumps, which move ions across membranes against their concentration gradient and use ATP as their energy source.
The Na + /K + -pump, also called 3Na + /2 K + ATPase, is a large transmembrane protein
with an intracellular ATP-binding site. Upon binding of ATP, the transporter opens
towards the cell interior and binds three Na + -ions from the cytoplasm. It then changes
conformation and opens towards the outside of the cell, where the Na + -ions are released.
This means that Na + -ions have passed through the membrane against their concentration
gradient of 150 mM (outside) versus 12 mM (inside). ATP is hydrolysed and then the
pump, now outwardly open, binds two K + -ions. As a result, the pump changes conformation and opens towards the inside, releasing K + into the cell. This process thus also works
against the K + concentration gradient of 140 mM inside and 4 mM outside the cell (Skou
and Esmann 1992). Similarly, ATP-driven Ca 2+ -pumps keep a low Ca 2+ concentration in
the cytoplasm by constantly pumping it out of the cell, where the concentration of Ca 2+ is
up to more than 10, 000 times higher. In addition, Ca 2+ -ions are stored in the endoplasmic
Chapter 4 · Ion Channels
4
evokes transcriptional, metabolic or behavioural responses in target cells. GPCRs activated by neuromodulators are often also found in presynaptic membranes (Civelli 2012).
Interestingly, transmitter molecules may act on LGICs and also on GPCRs as we will see
later, for instance, for GABA, glutamate, acetylcholine and serotonin.
Most neurotransmitters and neuromodulators are stored in vesicles at presynaptic
axon terminals. Many of these vesicles are already tethered to the membrane and ready to
be released. The amount of neurotransmitter available for binding to receptors on the
postsynaptic membrane depends on:
1. The frequency of arriving action potentials leading to their release.
2. The retrieval of the neurotransmitter back into the presynaptic neuron.
3. The inclusion of neurotransmitters into neuronal storage granules.
4. The degradation of the neurotransmitter within the synaptic cleft or in the cytoplasm
of the neuron.
Vesicle fusion and transmitter release occur after the action potential arrives. A voltagedependent Ca 2+ -channel (see later) opens, and Ca 2+ flows into the cytoplasm. Ca 2+ -ions
provide the trigger for the excitatory machinery to release the content of neurotransmitter
vesicles. Most neurotransmitters and neuromodulators will be retrieved after their release.
For this task, presynaptic membranes have specific transporters, e.g. the dopamine transporter DAT. Cytoplasmic neurotransmitters are transported into storage granules by specific symporters, e.g. the vesicular monoamine transporter VMAT. Degradation of
synaptic transmitters occurs through enzymes that are secreted into the synaptic cleft.
One example is the acetylcholine esterase, which cleaves the neurotransmitter acetylcholine into acetate and choline.
4.2 Membrane Potential and Electrochemical Gradient
The basis for the function of voltage-gated ion channels is the electrochemical gradient
across the plasma membrane. Such a gradient exists in all cells of the body, in muscle and
gland cells as well as in excitable cells, like nerve cells, where it is used for electrochemical
signalling, e.g. the generation of action potentials. The electrochemical gradient is due to
differences in the concentration of Na + , K + and Ca 2+ ions between the cytoplasm and the
extracellular space. These differences are maintained in all cells. They are generated by
ATP-dependent ion pumps, which move ions across membranes against their concentration gradient and use ATP as their energy source.
The Na + /K + -pump, also called 3Na + /2 K + ATPase, is a large transmembrane protein
with an intracellular ATP-binding site. Upon binding of ATP, the transporter opens
towards the cell interior and binds three Na + -ions from the cytoplasm. It then changes
conformation and opens towards the outside of the cell, where the Na + -ions are released.
This means that Na + -ions have passed through the membrane against their concentration
gradient of 150 mM (outside) versus 12 mM (inside). ATP is hydrolysed and then the
pump, now outwardly open, binds two K + -ions. As a result, the pump changes conformation and opens towards the inside, releasing K + into the cell. This process thus also works
against the K + concentration gradient of 140 mM inside and 4 mM outside the cell (Skou
and Esmann 1992). Similarly, ATP-driven Ca 2+ -pumps keep a low Ca 2+ concentration in
the cytoplasm by constantly pumping it out of the cell, where the concentration of Ca 2+ is
up to more than 10, 000 times higher. In addition, Ca 2+ -ions are stored in the endoplasmic
Chapter 4 · Ion Channels