Overview:    The concept of an ion channel had to await the acceptance by the scientific community of the existence of ions as well as the notion that cells are surrounded by a fatty membrane bilayer.   The emergence of both ion and cell membrane concepts can be traced back to the late 1800s.    Prior to this time, the existence of discrete individual molecules with a net charge (positive or negative ions) was largely in doubt, as was the nature of the barrier surrounding individual living cells.   We now know that, given the structure of atoms and molecules, which are themselves composed of positive as well as negative particles (protons and electrons, respectively),  ions are not only possible, but a common everyday experience,   especially in aqueous solutions such as those which surround living cells.    Thanks in large part to the revolution which was taking place in chemistry by the late 1700s due to Lavisouir and others, and to the joining of the by then well-established field of physics with the fields of chemistry and biology about that same time, the 19th Century would prove to be a watershed of knowledge for scientists.     When Luigi Galvani publicized to the world that electricity could induce a biological response in a frog's leg, in a way it could be said that he was studying ion channels for the first time, albeit indirectly.      


EARLY ION CHANNEL WORK:    People had been interested in understanding how nerve and muscle cells work at least since Galen's time as far back as the Roman Empire.   In 1759, Michel Adanson was the first to propose that the newly invented Leyden jar capacitor was identical in principle to the way an electric eel stores electricity within itself.  Not long afterwards, Volta, the inventor of the battery, noticed that there existed similarities in organization between the fish's electric organs and the batteries he was the first to build.  When Galvani published his results using electrical current in 1791  to make a dead frog's legs twitch, it encouraged many to try and explain how electrical current helps nerve cells transmit messages to muscles, as well as encouraging a cottage industry of medical frauds intent on using electricity to "cure" all types of ills.  

In Galvani's time, electricity was still thought of as a kind of "fluid", and this line of reasoning allowed for the ancient Roman belief that hollow nerve cells transmitting some sort of fluid messenger to other parts of the body be incorporated more easily into science of the late 18th Century.    The first quantitative measurements involving electrical activity in animal cells wouldn't be done until the late 1800s.    And even these later experiments lacked the important aspect of time-resolution which is now known to be necessary for accurately describing biologically derived electrical phenomena;  and it was mainly due to the limits of moving coil galvanometers.    The development of the thermionic values and the cathode ray oscilloscope, which would allow greater time-resolution of the experiment as well as greater reproducibility between different experiments, would have to wait until the 1920s.    As surprisingly accurate as these early results would be, the ability to measure the voltage of a cell membrane directly would remain impossible without electrodes small enough to insert directly inside the cell itself.

The mystery which remained throughout most of the 1800s concerned the nature of the electrical signal.    Were nerve cells analogous to small copper wire conductors?   Or was the situation more complex, such as the way two different chemicals were able to create electricity; as in a battery?     It would turn out to be the chemical explanation that was the correct one (i.e. ion flow in and out of nerve and muscle cells through ion channels).  As early as 1817 the great Swedish chemist Berzelius suggested that the electric eel's current was "elicited by an organic chemical process."      Italian physicist Leopoldo Nobili, in 1827, using his newly refined galvanometer which corrected for the earth's magnetic field, was the first to report measuring the current in a frog using any kind of an instrument.   Called the "astatic galvanometer", it was made of two coils of wire wound in opposite directions.  It allowed for canceling of the earth's magnetic field.   Following up on Nobili's work, in 1838 Carlo Matteucci measured current (which we now know to be ions) which leaking out of injured muscles, and by the century's end would form the basis for the important concept of the "resting potential" of both muscle and nerve cells.   Matteucci also went on to discover that muscle cells, after stimulation by a nerve, produce a current of their own.   In some of his experiments, he used an ingenious detector called the "galvanic frog", which was simply a severed leg from a frog with the nerve exposed which would twitch each time it detected a current; in this case, a current issuing from the stimulated muscle of another frog.   This muscle-generated current is now known as the "action potential".    Matteucci would also discover that he could simply change the pH of the solution surrounding the muscle tissue and it would illicit a contraction in the muscle just as the nerve did.   It was becoming more and more clear that the phenomenon underlying muscle and nerve cell excitation was chemical in nature.

Instrument Helmholtz used for determining the velocity of nerve cell conduction in 1850.   When the muscle (M) contracts, it signals this to (E), the galvanometer.  (N) is the nerve. (from: "a history of neurophysiology" by Mary A.B. Brazier) 


In 1850, Helmholtz succeeded in determining the velocity of the electric signal on a nerve cell and realized that it traveled much too slowly to be due simply to conduction such as occurs in a metal wire.    Nerves didn't act like carriers of electrical current as a wire did.   As so often happens in science, his sensitive measurements were made possible due to improvements in instrumentation; in this case, the galvanometer  (a current-sensing device invented in 1820).  But even after the refinement of the galvanometer, two experimental problems would remain to plague future investigators:   the problem of polarization (and the secondary currents it induces) on the experiment, which is caused by contaminated electrodes, and the problem that too much emphasis was being placed on the physiological significance of the electric current that was present in frog's legs while at rest.    In summary, the work during the first half of the 19th Century was pointing slowly towards some kind of an underlying chemical process that was taking place in nerve and muscle tissue as opposed to simple conduction or any kind of supernatural "vitalism"; i.e. forces unique only to living things.  

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