Celltocell Communication

Through either neurotransmitter release at chemical synapses or current flow through gap junctions, ligand-gated or voltage-gated channels open and elicit postsynaptic potentials. Postsynaptic potentials alter the probability that an action potential will be produced in the postsynaptic cell. If there is depolarization of the membrane, the potential is termed an excitatory postsynaptic potentials (EPSP), whereas, if there is hyperpolarization, the potential is called an inhibitory postsynaptic potential (IPSP). EPSPs bring the membrane potential closer to threshold for action potential generation, whereas IPSPs keep the membrane potential more negative than the threshold potential. In chemical synapses, whether the event is an EPSP or IPSP depends on the neurotransmitter released and the type of postsynaptic receptor activated. In the cerebral cortex, approx 90% of neurons (principal neurons) synthesize and release glutamate, the principal CNS excitatory neurotransmitter. The remaining neuronal populations (interneurons) release GABA, the principal inhibitory neurotransmitter of the cortex.

Direct electrical transmission from one cell to another occurs through gap junctions. Gap junctions consist of hexameric complexes formed by the close juxtaposition of pores consisting of proteins called connexons that span the neuronal membrane. The pore of a gap junction is larger than the pores of voltage-gated ion channels and can, therefore, transfer larger substances between cells, including intracellular metabolites. Electrical transmission across gap junctions occurs rapidly because passive current flow across the gap junction is virtually instantaneous. Gap junctions seem to have an important role in the synchronization of neuron firing, particularly in interneuronal networks.

Chemical synapses have a wider spacing between cells, termed the synaptic cleft, and operate through release of neurotransmitter stored in vesicles. The neurotransmitter diffuses from the presynaptic membrane to the postsynaptic membrane. Neurotransmitter release occurs when an action potential reaches the presynaptic terminal and initiates the opening of voltage-gated Ca2+ channels. This permits a rapid influx of Ca2+ into the presynaptic terminal. Elevation of intracellular Ca2+ causes synaptic vesicles to fuse with the plasma membrane of the presynaptic neuron. There are a number of calcium-binding proteins that participate in the cascade of events that lead to neurotransmitter release. The fusion of the vesicular and neuronal membranes allows release of the neurotransmitter. Figure 4 illustrates the process of neurotransmitter release.

Excitatory synaptic transmission is mediated by glutamate acting on target postsynaptic neurons via three types of ionotropic receptors, named after their selective agonists (a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid [AMPA], kainic acid [KA], and N-methyl-D-aspartate [NMDA]). Although all types of glutamate receptors respond to glutamate, they have individual characteristics. The AMPA receptor responds rapidly to glutamate with opening of

Fig. 4. Synaptic neurotransmission. An action potential travels down the axon until it reaches the synapse. The depolarization causes voltage-gated Ca2+ channels to open. The influx of Ca2+ results in high concentrations of Ca2+ near the active zone (A). This triggers fusion of vesicles with neurotransmitter to the presynaptic cell membrane and emptying of the vesicles into the synaptic cleft (B). The neurotransmitter crosses to the postsynaptic membrane and results in depolarization of the membrane if it is an excitatory neurotransmitter. With glutamate release, there is binding of the ligand to post-synaptic receptors (AMPA, KA, or NMDA) with subsequent inflow of Na+ ions. Modified from Kandel et al., 2000 with permission.

Fig. 4. Synaptic neurotransmission. An action potential travels down the axon until it reaches the synapse. The depolarization causes voltage-gated Ca2+ channels to open. The influx of Ca2+ results in high concentrations of Ca2+ near the active zone (A). This triggers fusion of vesicles with neurotransmitter to the presynaptic cell membrane and emptying of the vesicles into the synaptic cleft (B). The neurotransmitter crosses to the postsynaptic membrane and results in depolarization of the membrane if it is an excitatory neurotransmitter. With glutamate release, there is binding of the ligand to post-synaptic receptors (AMPA, KA, or NMDA) with subsequent inflow of Na+ ions. Modified from Kandel et al., 2000 with permission.

channels permeable to Na+ and K+, resulting in depolarization. One synapse contains tens of AMPA receptors on the postsynaptic membrane, and current summation leads to an EPSP of approx 1 mV. As a result, simultaneous activation of several excitatory synapses is necessary to sufficiently activate a postsynaptic neuron to action potential threshold. Kainate receptors are similar to AMPA receptors but have slower kinetics. The third type of glutamate ionotropic receptor—the NMDA receptor—may not directly participate in information processing but seems to play a critical role in synaptic plasticity. The NMDA channel has characteristics of both a ligand-activated and voltage-sensitive channel. At resting potential, Mg2+ sits in the channel, blocking the flow of ions. Only with depolarization of the membrane is Mg2+ displaced and Na+ and Ca2+ ions able to cross the channel. The high permeability of the NMDA receptor to Ca2+ underlies its role in synaptic plasticity, such as long-term potentiation of synaptic strength, which is hypothesized to participate in learning and memory.

GABA is the principal inhibitory transmitter of the brain. Inhibitory synapses made by interneurons and using GABA as their transmitter use two types of receptors, GABAA and GABAB receptors. GABAA receptors are ligand-gated ion channels, whereas GABAB receptors are metabotropic receptors (see next paragraph). GABAa receptors are inhibitory because their associated ion channels are permeable to Cl_. Because the reversal potential for Cl_ is more negative than the threshold for neuronal firing, Cl_ flow hinders action potential generation. Activation of GABAb receptors results in opening of K+ channels that also inhibits the postsynaptic cell. In the spinal cord, GABA and glycine act as inhibitory transmitters.

Metabotropic receptors differ from ionotropic receptors in that they affect ion channels via the activation of G proteins. All metabotropic receptors are part of a superfamily of G protein-coupled receptors. In certain cases, the activation of G proteins by metabotropic receptors allows binding of activated G protein subunits directly to ion channels (this mechanism, for instance, operates in GABAb receptor-mediated opening of K+ channels). In other cases, metabotropic receptors can be coupled to ionic channels via second messengers, such as cAMP or cGMP. Metabotropic receptors can also couple to intracellular effector enzymes. Activation of protein kinases can then phosphorylate ion channels or other proteins closely associated with ion channels, thereby altering channel function.

There are five biogenic amine neurotransmitters: three catecholamines, norepinephrine, epinephrine, and dopamine; and histamine and serotonin. Dopamine plays a role in control of body movements, and norepinephrine and serotonin in the modulation of sleep and wake-fulness. The role of epinephrine and serotonin is less clear.

Acetylcholine is concentrated in two major CNS loci, the forebrain nuclear complex and the cholinergic nuclei of the brainstem tegmentum. Although not yet fully understood, it is known that acetylcholine is in involved in pain and chemosensory pathways as well as memory. Interestingly, autosomal dominant nocturnal frontal lobe epilepsy has been linked to chromosome 20q13.2 and a mutation in the gene CHRNA4 encoding the a4-subunit of a neuronal nicotinic acetylcholine receptor. Nicotinic cholinoreceptors are enriched in interneurons and deficiency in the excitation of these inhibitory cells possibly underlies the enhanced excitability thought to be operant in epilepsy.

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