Medical brain Notes 3

  The ionic basis of cell excitation Excitable cells – nerve cells and the various types of muscle cells – have a prominent role in the physiological processes that are targeted by drug therapy. We will therefore spend some time looking at how electrical cell excitation works.   The fundamental prerequisite of excitability is the presence of a membrane potential. A membrane potential is present in apparently all living cells. In non-excitable cells, the ori-entation of the membrane potential is always such that the cell interior is electrically negative against the outside. This orientation also prevails in excitable cells that are not cur-rently excited, i.e. currently are at their  resting potential . One fundamental function of this negative-inside mem-brane potential in all cells consists in powering active trans-port, usually in the form of sodium cotransport. Membrane potentials also exist across membranes within cells. An important example is the potential across t...

  Ion gradients across the cell plasma membrane All membrane potentials depend on the existence of ion gradients across the membrane in question. The major ion species that shape the form of both resting potentials and action potentials are K + , Na + , Ca ++ , and Cl - . The ion gradi-ents result from the activities of three types of membrane proteins:   1.Ion pumps. These proteins use metabolic energy in the form of ATP to transport ions against their concentra tion gradients. Quantitatively the most important ion pump is Na + /K + -ATP'-ase (Figure 4.1), which transports both sodium and potassium against their respective gra-dients (table 4.1). In addition, various types of calcium pumps are found in the cytoplasmic, ER and mitochon-drial membranes; the direction of Ca ++  transport is al-ways from the cytosol to the other compartment.   2.    Exchange- and co-transporters. These link the gradients of different ion species to one another, so that gradien...

  The physics of membrane potentials Both the resting and the action potential are diffusion potentials. A diffusion potential arises at a membrane if   1.    the membrane is selectively permeable for one or a few ion species, 2.    ls exist will therefore have a say in determining the membrane potential. Furthermore, as ion channels open and close, the changing permeabilities can shift the weight from one ion to the other. The most important example is the transient opening of sodium channels, which according to the Goldman equation will cause the membrane potential to shift toward the equilibrium potential.   Figure 4.2a shows a membrane that has an ion gradient across it but is entirely impermeable; this will result in no membrane potential, as long as the numbers of anions and cations are the same within each adjoining compartment. In Figure 4.2b, the membrane has been rendered perme-able by a large, non-selective hole; both anions and cations are ...

  Voltage-gated cation channels and the action potential   While transporters and leak channels shape the resting po-tential, the action potential is the fiefdom of the gated channels. Voltage-gated channels, in particular, are important for the spreading of action potentials over the surface of an entire cell. In most excitable cells, there are high numbers of voltage-gated channels for both sodium and potassium (and, in fact, several subtypes of both). In addition, voltage-gated Ca ++  channels prominently occur in heart and smooth muscle cells. In the resting state, the voltage-gated channels are closed. As stated before, the negative-inside potential at rest is due to the occurrence of K +  leak channels (Figure 4.5a). The voltage-gated channels enter into the picture when a change occurs in the surrounding electrical field. The channel pro-teins possess mechanically flexible domains that carry an electrical charge, and that will thus change conformation in respo...

  The origin of cell excitation The mechanisms we have discussed above account for the propagation and for the termination of the action potential. However, so far we have relied on external electrodes for its initiation. Under physiological conditions, action potentials can be evoked in various ways. The first, very important means of action potential genera-tion consists in synaptic transmission. A synapse connects a presynaptic cell (always a neuron) to a postsynaptic cell (a neuron or muscle cell). In brief, a synapse works as fol-lows:   1.    Excitation of the presynaptic cell leads to the release of a neurotransmitter substance.   2.    The neurotransmitter binds to a receptor on the postsy-naptic cell, very commonly a ligand-gated channel.   3.    The receptor channel opens and locally depolarizes the membrane.   4.    The local depolarization is picked up by adjacent voltage-gated channels and propagated across th...