Sn2

interneuron illustrated in Fig. 21C. Normally, this interneuron would be activated by summating EPSPs from converging afferent fibers. These EPSPs would summate in space and time such that the membrane potential of the interneuron would reach threshold and fire an action potential. This step can be bypassed by artificially depolarizing the interneuron to initiate an action potential. The consequences of that action potential from the point of view of flexor motor neurons are illustrated in Fig. 21C. The action potential in the interneuron produces a transient increase in the membrane potential of the motor neuron. This transient hyperpolarization (the IPSP) looks very much like the EPSP, but it is reversed in sign.

What are the ionic mechanisms for these fast IPSPs and what is the transmitter substance? Because the membrane potential of the flexor motor neuron is approximately —65 mV, one might expect an increase in the conductance to some ion (or ions) with an equilibrium potential (reversal potential) more negative than —65 mV. One possibility is K+; indeed, the K+ equilibrium potential in spinal motor neurons is approximately —80 mV. A transmitter substance that produced a selective increase in K+ conductance would lead to an IPSP. The K+-conductance increase would move the membrane potential from —65 mV toward the K+ equilibrium potential of —80 mV. Although an increase in K+ conductance mediates IPSPs at some inhibitory synapses, it does not do so at the synapse between the inhibitory interneuron and the spinal motor neuron. At this particular synapse, the IPSP seems to be due to a selective increase in Cl— conductance. The equilibrium potential for Cl— in spinal motor neurons is approximately —70 mV. Thus, the transmitter substance released by the inhibitory neuron diffuses across the cleft and interacts with receptor sites on the postsynaptic membrane. These receptors are coupled to a special class of receptor channels that are normally closed, but when opened they become selectively permeable to Cl—. As a result of the increase in Cl— conductance, the membrane potential moves from a resting value of —65 mV toward the Cl— equilibrium potential of —70 mV.

Like the case of the sensory neuron-spinal motor synapse, the transmitter substance released by the inhibitory interneuron in the spinal cord is an amino acid, but in this case the transmitter is glycine. Indeed, glycine is used frequently in the CNS as an inhibitory transmitter, most often in the spinal cord. The most common transmitter associated with inhibitory actions in many areas of the brain is gamma aminobutyric acid (GABA). The agents bicuculline and picrotoxin are specific blockers of the actions of GABA. Strychnine is a specific blocker of the actions of glycine.

General Features of lonotropic-Mediated PSPs and the Molecular Biology of the Receptor-Channel Complexes

The general features of ionotropic receptors in the CNS are similar to those of the ligand-gated ACh receptor-channel found in the skeletal muscle. In particular, ionotropic receptors in the CNS for ACh, glycine, and GABA are made up of multiple subunits (usually a pentameric structure), with each of the subunits having four membrane-spanning regions (see Fig. 12).

Neuronal nicotinic ACh receptors and GABA receptors have been particularly well characterized. Unlike the skeletal muscle ACh receptor, which is made up of four types of subunits (a, fi, <5, and e or y), the neuronal ACh receptor is made up of only two types of subunits (a and fi). A considerable diversity of channel properties is possible, however, because there are at least eight different a subunits and three different fi subunits. Indeed, it has been estimated that the combinatorial possibilities could result in more than 4000 different types of receptors. The ionotropic GABA receptor (called GABAA) are generally comprised of a combination of three different subunits, a, fi, and y, in a stoichiometry of 2a2fi1y. Each subunit type has multiple isoforms; therefore, the considerable diversity of GABAa receptors observed in vivo appears to be due to the various stoichiometric combinations of different subunit isoforms.

Glutamate is the predominant transmitter with excitatory actions in the CNS, and in recent years insights into the structural characteristics of its receptors have been obtained. Like many other ion channels, ionotropic glutamate receptors are homo- or hetero-multimeric proteins consisting of four subunits. Each subunit consists of an extracellular amino-terminal domain, three transmembrane domains, a re-entrant loop that forms the channel pore, and a cytoplasmic carboxy terminal. Although the structure of the full-length channel has not yet been resolved, the crystal structure of the amino-terminal ligand-binding region has been resolved and conformational changes associated with ligand binding have been identified. However, the mechanisms by which ligand binding drives channel opening are not fully understood. Ionotropic glutamate receptors can be divided into two broad classes based on their sensitivity to the agonist N-methyl-D-aspartate (NMDA) and are referred to as NMDA and non-NMDA receptors. Both types are located throughout the nervous system, but their relative abundance differs. Non-NMDA glutamate receptors have the functional properties described previously for fast ionotropic-mediated synaptic actions at the sensory neuron-motor neuron synapses (e.g., Fig. 21B). Specifically, as a result

6. Neuromuscular and Synaptic Transmission

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