Neurotransmitters and Receptor and Transport Proteins in Signal Transmission at Synapses
■ Neurotransmitter receptors fall into two classes: ligand-gated ion channels, which permit ion passage when open, and G protein-coupled receptors, which are linked to a separate ion channel.
■ At synapses impulses are transmitted by neurotransmit-ters released from the axon terminal of the presynaptic cell and subsequently bound to specific receptors on the post-synaptic cell (see Figure 7-31).
■ Low-molecular-weight neurotransmitters (e.g., acetyl-choline, dopamine, epinephrine) are imported from the cy-tosol into synaptic vesicles by H+-linked antiporters. V-class proton pumps maintain the low intravesicular pH that drives neurotransmitter import against a concentration gradient.
■ Arrival of an action potential at a presynaptic axon terminal opens voltage-gated Ca2+ channels, leading to a localized rise in the cytosolic Ca2+ level that triggers exocy-tosis of synaptic vesicles. Following neurotransmitter release, vesicles are formed by endocytosis and recycled (see Figure 7-42).
■ Coordinated operation of four gated ion channels at the synapse of a motor neuron and striated muscle cell leads to release of acetylcholine from the axon terminal, depolarization of the muscle membrane, generation of an action potential, and then contraction (see Figure 7-44).
■ The nicotinic acetylcholine receptor, a ligand-gated cation channel, contains five subunits, each of which has a transmembrane a helix (M2) that lines the channel (see Figure 7-45).
■ A postsynaptic neuron generates an action potential only when the plasma membrane at the axon hillock is depolarized to the threshold potential by the summation of small depolarizations and hyperpolarizations caused by activation of multiple neuronal receptors (see Figure 7-48).
In this chapter, we have explained certain aspects of human physiology in terms of the action of specific membrane transport proteins. Such a molecular physiology approach has many medical applications. Even today, specific inhibitors or activators of channels, pumps, and transporters constitute the largest single class of drugs. For instance, an inhibitor of the gastric H+/K+ ATPase that acidifies the stomach is the most widely used drug for treating stomach ulcers. Inhibitors of channel proteins in the kidney are widely used to control hypertension (high blood pressure). By blocking resorption of water from the forming urine into the blood, these drugs reduce blood volume and thus blood pressure. Calcium-channel blockers are widely employed to control the intensity of contraction of the heart. And the Na+-linked symport proteins that are used by nerve cells for reuptake of neuro-transmitters are specifically inhibited by many drugs of abuse (e.g., cocaine) and antidepression medications (e.g., Prozac).
With the completion of the human genome project, we are positioned to learn the sequences of all human membrane transport proteins. Already we know that mutations in many of them cause disease. For example, mutation in a voltage-gated Na+ channel that is expressed in the heart causes ventricular fibrillation and heart attacks. Mutations in other Na+ channels, expressed mainly in the brain, cause epilepsy and febrile seizures. In some cases the molecular mechanisms are known. One type of missense mutation in a Na+ channel that causes epilepsy affects the voltage dependence of channel opening and closing; another slows inactivation of the channel at depolarizing potentials, prolonging the influx of Na+ ions. Studies in mice expressing mutant forms of these and many other membrane transport proteins are continuing to provide clues to their role in human physiology and disease.
This exploding basic knowledge will enable researchers to identify new types of compounds that inhibit or activate just one of these membrane transport proteins and not its homologs. An important challenge, however is to understand the role of an individual transport protein in each of the several tissues in which it is expressed. As an example, a drug that inhibits a particular ion channel in sensory neurons might be useful in treatment of chronic pain, but if this channel also is expressed in certain areas of the brain, its inhibition may have serious undesired actions ("side effects").
A real understanding of the function of nerve cells requires knowledge of the three-dimensional structures of many different channels, neurotransmitter receptors, and other membrane proteins. Determination of the structure of the first voltage-gated K+ channel should illuminate the mechanisms of channel gating, opening, and inactivation that may also apply to other voltage-gated channels. Similarly, the nicotinic acetylcholine, glutamate, GABA, and glycine receptors are all ligand-gated ion channels, but it is disputed whether they all have the same overall structures in the membrane. Resolving this issue will also require knowledge of their three-dimensional structures, which, in addition, should tell us in detail how neurotransmitter binding leads to channel opening.
How does a neuron achieve its very long, branching structure? Why does one part of a neuron become a dendrite and another an axon? Why are certain key membrane proteins clustered at particular points—neurotransmitter receptors in postsynaptic densities in dendrites, Ca2+ channels in axon termini, and Na+ channels in myelinated neurons at the nodes of Ranvier? Such questions of cell shape and
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