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chemicals that interact with the conductance anions. Studies of the detailed time-course
pathway, even the electrical-potential of responses to acetylcholine indicated that
difference itself, may have great effects on this channel had not only “open” and
the conductance of a membrane to an ion. “closed” states, but also a special
These types of influences on conductances “desensitized” state that had to revert slowly
underlie much of biological signaling. For to the “closed” state before the channel
example, determining experimentally how could open again.
ion conductances change with membrane This concept of molecular-scale channels,
potential, ion concentrations, and time based on work at the cellular level, has now
formed the basis for Hodgkin and Huxley’s been amply verified at the molecular scale.
explanation of action potentials in nerves. Recordings have been made of currents
through individual channels; the gene and
Biological ion channels protein sequences of many types of ion
The pioneering work of Hodgkin, Huxley channels have been determined, including
and Katz in the late 1940s and early 1950s channels directly responding to
indicated that ion flow across cell acetylcholine or to other neurotransmitter
membranes was mediated by individual molecules; physical subunit structures have
molecular-scale aqueous “channels” across been found that correspond to the type of
the membrane. Different channels were cooperatively-acting subunits hypothesized
thought to have different selectivity among by Hodgkin, Huxley and Katz; natural and
ions—e.g., some selective for potassium, induced mutations of channel sequences
others for sodium ion. Whether a channel have begun to demonstrate the particular
was “open” or “closed” depended on the portions of the channel proteins that provide
membrane potential, with the kinetics of selectivity among ions, sensitivity to
response to a change in membrane potential chemical ligands, and dependence on
differing among channel types. The electrical potential difference across the
experimentally-determined characteristics of membrane in which the channels are
ion flow across squid giant axon membranes embedded.
could be modeled by cooperative processes,
in which a number of subunits of a channel Some types of channels are affected more
needed all to be in particular voltage- indirectly by external chemical signals. In
dependent states for the channel to be open. these cases, an external chemical signal
binds to a non-channel membrane protein
This conceptual approach provided the that initiates a series of intracellular
first quantitative description of the chemical reactions. The “second
mechanism of the “action potential” that messengers” thus produced by the cell then
transmits electrical signals along nerve affect the states of ion channels. For
axons. Work by Katz and his colleagues example, although acetylcholine binds
then demonstrated that the signal from a directly to proteins that form an ion channel
nerve that makes a skeletal muscle contract in skeletal muscle, it does not bind directly
also works via a channel. In this case, a to ion channels on “smooth muscle” cells of
channel on the surface membrane of the internal organs. In smooth muscle,
muscle cell is opened by a chemical signal, acetylcholine exerts its effects through
acetylcholine, which is released by the nerve “second messengers” instead.
terminals in response to an action potential
in the nerve. The acetylcholine-sensitive
channel on the muscle membrane was found
to be permeant to many cations, but not to
Furthermore, not all processes that transport potentials were studied long before it
ions across the plasma membrane result in a became technically possible to measure
current. Neither the Na+-H+ exchanger potential differences across cell membranes.
involved in acid-base balance nor the Measurements of the electrocardiogram and
Na+-K+-2Cl- cotransporter important in renal early measurements of “receptor potentials,”
and inner-ear function carries net current. the electrical events associated with sense
Yet both can affect ion concentrations in organs, were not accomplished by sticking
cells, and thus the Nernst equilibrium an electrode into a cell. These rather were
potentials for those ions and the whole-cell recordings taken by electrodes sitting on the
zero-net-current resting potential. Despite surface of the body or perhaps within a
these complications, a conductance- tissue but not within a cell.
weighted average of Nernst potentials is a Even today, many of the most common
good place to start for an estimate of a cell’s electrical measurements associated with
membrane potential. studies of auditory function are
extracellular, not intracellular. The
What comes in must go out compound action potential, the cochlear
Although ion channels may best be microphonic, the auditory brainstem
studied when the experimenter controls ion response, even the endocochlear potential
concentrations and potentials, that is not are all extracellular recordings. How do
how they work in vivo. Channels in the these extracellular potentials correspond to
plasma membrane are in a structure that events going on across cell membranes?
surrounds the contents of the cell. If The best way to think about extracellular
situations change in one membrane location, potentials is to apply Ohm’s Law. A
leading say to a local inward current, there potential is the product of a current times a
must also be an outward current elsewhere resistance. An extracellular electrode
through the cell membrane to continue the records a potential difference from some
circuit. (The capacitance of cell membranes distant ground electrode located elsewhere
is important during transients, but steady- on the body or in a tissue bath. That
state current return will be via conductive extracellular potential difference is
paths.) For cells that are polarized, like hair determined by the resistance to current flow
cells, this means that we have to consider between the recording electrode and ground,
not only the specialized current entry and the current flowing past the recording
channels but also the (potentially quite electrode to ground.
different) current exit channels.
Furthermore, in this type of situation, there So for a fixed recording location, the
will be extracellular currents to complete the potential recorded from an extracellular
electrical circuit. Many electrical electrode is primarily determined by
measurements made in biological systems extracellular current flow. If enough cells
are effectively of these extracellular currents synchronously produce currents there may
rather than of electrical potential differences be enough net extracellular current to
across individual cell membranes. produce an appreciable extracellular
potential.
How many cells is enough? One cell can
Extracellular potentials
be enough: about 70 years ago, Alan
It’s simplest conceptually to start thinking Hodgkin forced the extracellular currents
about electrical potential differences across generated by a nerve axon to flow through a
a cell membrane. Nevertheless, bioelectric high enough extracellular resistance to make
reliable measurements and perform some the structure of cell membranes and proteins
elegant experiments on the conduction of in cell membranes. Chapter 11 deals with
action potentials even before intracellular ion transport, ion channels, action potentials,
recordings were possible. Millions of cells and synaptic function.
are involved in the electrocardiogram, which Introductory neuroscience texts also
represents the synchronized activity of cover this material. “Principles of Neural
muscle fibers in the heart. The classic Science” by Kandel, Schwartz and Jessell
receptor potential of the auditory system, the (McGraw-Hill, New York; 4th Edition,
“cochlear microphonic,” arises from 2000) is generally well written, though
synchronous currents passing through some voluminous. A particularly useful book
hundreds or thousands of hair cells when specifically on ion channels is “Ionic
they are stimulated by sound. Channels of Excitable Membranes” by B.
References Hille (Sinauer, Sunderland MA; 3rd Edition,
For a somewhat different perspective on 2001).
these topics, consult “The Molecular For further reading of research reviews or
Biology of the Cell” by Alberts et al. of classic experimental studies, consult the
(Garland, New York; 4th Edition, 2002), references at the end of Chapter 11 of
chapters 10 and 11. Chapter 10 deals with Alberts et al., or talk with one of the faculty.