Discovering the Brain (1992) / Chapter Skim
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5 From Chemistry to Circuitry
5 From Chemistry to Circuitry
Pages 67-85
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From page 67... ...
The scientific understancling of electricity in the nervous system has come a long way since the 1700s, when Luigi Galvani of Bologna noticed that disembodied frog legs hanging on copper hooks from an iron balcony would occasionally twitch, as if still animated. On the basis of this observation and subsequent experiments, he concluded that the motive force in the nervous system was electricity rather than the traditionally conceived "animal spirits." Galvani could scarcely have imagined the bacterial robots, electron diffraction microscopes, and positron emission tomography devices that would come to replace the accoutrements of an eighteenth-century Italian kitchen as the proper equipment for scientific observation.
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From page 69... ...
Pen-and-ink drawings were the first scientific illustrations to depict the actual structure of individual nerve cells. Several types of neurons are represented here; each has a recognizably thicker portion that is the cell body, and most have a single axon that projects like a thin wire.
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From page 70... ...
Conversely, drugs that inhibit the chemical breakdown of ACh and thus extend its action in the synaptic cleft are at least temporarily effective against myasthenia gravis; this is a crippling disease in which the body's own immune system attacks the receptor sites for ACh on the skeletal muscles. The muscles gradually weaken as they receive fewer synaptic transmissions, but clrugs such as eserine can effectively increase the amount of ACh available to the remaining receptor sites.
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From page 71... ...
Moreover, some of the factors that are undoubtedly important for mood are unquantifiable, invisible, and perhaps irreproducible for laboratory study. One point of wide consensus, however, is that depression can be helped by two classes of drugs: one class blocks an enzyme that would normally break down norepinephrine in the synaptic cleft, and the other slows the reuptake of norepinephrine into the presynaptic cell.
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From page 72... ...
Without the electrical insulation afforded by the myelin sheath, impulses travel at less than the lightning speed achieved by, say, signals to the motor neurons, but this seems appropriate to the more global and subjective areas of life regulatecl by serotonin.) The remarkable effects of lysergic acid diethylamide, or LSD, in even the tiniest quantities, are based on its strong chemical resemblance to serotonin; it is as if a full system of preexisting receptor sites lies ready for the drug's use.
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From page 73... ...
A third clue may be the ability of amphetamines, when taken in sufficient quantity, to bring on disturbances of the mind much like schizophrenia; it is known that amphetamines, or "uppers," increase the levels of dopamine available in the brain. To be sure, an illness as complex as schizophrenia cannot be reduced to a simple chemical explanation such as "excess of dopamine." The question remains open whether the schizophrenic brain suffers from too much dopamine, too many dopamine receptors, a standard quantity of receptors with abnormally high sensitivity, or some other dysfunction entirely—to say nothing of the important genetic, social, and psychological factors also under study.
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From page 74... ...
instead, an array of recent studies have yielded the view that the GABA receptor site is in fact a multifunctional set of proteins that contain the chloride ion channel and distinct subsites for binding of benzodiazepines, other tranquilizers such as barbiturates, and GABA itself. RECEPTORS PLAY AN ACTIVE PART The neurotransmitters discussed thus far are just a few of the ones that have been known for a relatively long time (at least a decade or two)
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From page 75... ...
In muscle cells, it acts directly, moving positively charged sodium ions into the cell and depolarizing it. In the brain, however, this transmitter works in tandem with a "second messenger," which conveys the signal inside the cell, sometimes amplifying it greatly in the process.
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From page 76... ...
Because of the great potential for amplifying the signal at each step (from first messenger to enzyme to cyclic AMP to protein kinase to phosphorylated protein to switched-on function) , just a few molecules of a neurotransmitter can cause target cells to produce several million molecules of a reaction substance in far less time than it takes to read about it.
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From page 77... ...
Or, to reframe the question, were the opiates gaining ready access by fitting into receptor sites that were there to serve some other built-in function? if so, the opiates must all be similar in structure which they are—and they must also resemble the "original" endogenous transmitters well enough to mislead the receptor sites.
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From page 78... ...
Robert Lefkowitz and his colleagues at the Howard Hughes Medical Institute at Duke University have been looking closely at epinephrine and norepinephrine receptor sites for several years practically the lifetime of this field so far. The adrenergic (epinephrine-using)
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From page 79... ...
The arrangement of seven membrane-spanning domains occurs widely throughout nature, in numerous guises. Many hormones, as well as transmitters, have receptors of this type; proteins called the opsins, which are precursors for the visual pigments, also fall in this category; and even in species as distant from ourselves as the slime mold, cyclic AMP is regulated through such a receptor.
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From page 80... ...
; the result is a chemical reaction that takes place inside the cell and, consequently, a change in the cell's activities. What all receptor sites apparently have in common is a molecular structure that extends across the cell membrane (gray bar)
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From page 81... ...
in the development of pharmaceutical aids to reduce desensitization and thereby prolong the therapeutic effect of some drugs, BARK and barrestin offer two targets that were completely unknown only a few years ago. THE INTRIGUING ROLE OF THE ION CHANNELS While the discovery of neurotransmitters and eluciciation of the structure of their receptor sites have been proceeding apace, another family of receptor sites is also becoming increasingly well known to neuroscience.
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From page 82... ...
Genetic studies have made it possible to clone several ion channels the optimum method for a close study of channel structure. Cloning of the sodium channel gene has revealed that it includes four domains, each of which spans the membrane multiple times.
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From page 83... ...
Diversity may also arise by another means: several of the relatively short sequences may coalesce in various ways to form a single potassium channel. The research team of Tinily Yeh fan, at Howard Hughes Medical Institute and the Departments of Physiology and Biochemistry at the University of California, San Francisco, set out to test this possibility.
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From page 84... ...
Snyder's research team used as their starting point the established fact that when the neurotransmitter glutamate binds to receptor sites, the calcium channels open and a great amount of cyclic GMP is produced. Once the investigators knew what to look for, they could follow two lines of evidence simultaneously: levels of citrulline and levels of cyclic GMP, both of which indicate the action of nitric oxide.
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From page 85... ...
This was a remarkably swift reaction, well within the time frame of some of the more brisk neurotransmitters. It appears that the nitric oxide-forming enzyme is switched on as soon as the calcium channels open, and it begins at once to produce nitric oxide at full speed, with some help from calmodulin, a calcium-binding protein.
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