Postsynaptic mechanisms
Neurotransmitters can either excite or inhibit the activity of a cell with which they are in contact. When an excitatory transmitter such as acetylcholine, or an inhibitory transmitter such as GABA, is released from a nerve terminal it diffuses across the synaptic cleft to the postsynaptic membrane, where it activates the receptor site. Some receptors, such as the nicotinic receptor, are directly linked to sodium ion channels, so that when acetylcholine stimulates the nicotinic receptor, the ion channel opens to allow an exchange of sodium and potassium ions across the nerve membrane. Such receptors are called ionotropic receptors. The generation of action potentials by nerve axons and muscle fibres was first described by the German physiologist Emil DuBois-Reymond in 1849.However, it was not until over a century later that the underlying mechanism was explained in terms of the properties of the specific membrane proteins forming the voltage-gated ion channels of sodium and potassium ions. Second messenger system When receptors are directly linked to ion channels, fast excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs) occur. However, it is well established that slow potential changes also occur and that such changes are due to the receptor being linked to the ion channel indirectly via a second messenger system.For example, the stimulation of b- adrenoceptors by noradrenaline results in the activation of adenylate cyclase on the inner side of the nerve membrane. This enzyme catalyses the breakdown of ATP to the very labile, high-energy compound cyclic 3,5-adenosine monophosphate (cyclic AMP). Cyclic AMP then activates a protein kinase which, by phosphorylating specific membrane proteins, opens an ion channel to cause an efflux of potassium and an influx of sodium ions. Such receptors are termed metabotropic receptors.
Many monoamine neurotransmitters are now thought to work by this receptor-linked second messenger system. In some cases, however, stimulation of the postsynaptic receptors can cause the inhibition of adenylate cyclase activity. For example, D2 dopamine receptors inhibit, while D1 receptors stimulate, the activity of the cyclase. Such differences have been ascribed to the fact that the cyclase is linked to two distinct guanosine triphosphate (GTP) binding proteins in the cell membrane, termed GI and GS. The former protein inhibits the cyclase, possibly by reducing the effects of the GS protein which stimulates the cyclase.The possible role of the family of protein kinases which translate information from the second messenger to the membrane proteins. Many of these kinases are controlled by free calcium ions within the cell. It is now established that some serotonin (5-HT) receptors, for example, are linked via G proteins to the phosphatidyl inositol pathway which, by mobilizing membrane-bound diacylglycerol and free calcium ions, can activate a specific protein kinase C. This enzyme affects the concentration of calmodulin, a calcium sequestering protein that plays a key role in many intracellular processes. Structurally G-proteins are composed of three sub-units termed alpha, beta and gamma. Of these, the alpha sub-units are structurally diverse so that each member of the G-protein super-family has a unique alpha sub-unit. Thus the multiplicity of the alpha, and to a lesser extent the beta and gamma, sub-units provides for the coupling of a variety of receptors to different second messenger systems. In this way, different receptor types are able to interact and regulate each other, thereby allowing for greater signal divergence, convergence or filtering than could be achieved solely on the basis of the receptor diversity. The functional response of a nerve cell to a transmitter can change as a result of the receptor becoming sensitized or desensitized following a decrease or increase, respectively, in the concentration of the transmitter at the receptor site. Among those receptors that are directly coupled to ion channels, receptor desensitization is often rapid and pronounced.Most of the experime ntal evidence came initially from studies of the frog motor end-plate, where it was shown that the desensitization of the nicotinic receptor caused by continuous short pulses of acetylcholine was associated with a slow-conformational change in that the ion channel remained closed despite the fact that the transmitter was bound to the receptor surface.A similar mechanism has also been shown to occur in brain cells. For example, continuous exposure of b-adrenoceptors on rat glioma cells in vitro results in a rapid reduction in the responsiveness of the receptors. This is followed by a secondary stage of desensitization, whereby the number of b-receptors decreases. It seems likely that the receptors are not lost but move into the cell and are therefore no longer accessible to the transmitter.It must be emphasized that there is considerable integration and modulation between the various second messenger systems and these interactions lead to cross-talk between neurotransmitter systems. Such cross-talk between the second messenger systems may account for changes in the sensitivity of neurotransmitter receptors following prolonged
stimulation by an agonist whereby a reduction in the receptor density is associated with a reduced physiological response (also termed receptor down-regulation).
Neurotransmitters can either excite or inhibit the activity of a cell with which they are in contact. When an excitatory transmitter such as acetylcholine, or an inhibitory transmitter such as GABA, is released from a nerve terminal it diffuses across the synaptic cleft to the postsynaptic membrane, where it activates the receptor site. Some receptors, such as the nicotinic receptor, are directly linked to sodium ion channels, so that when acetylcholine stimulates the nicotinic receptor, the ion channel opens to allow an exchange of sodium and potassium ions across the nerve membrane. Such receptors are called ionotropic receptors. The generation of action potentials by nerve axons and muscle fibres was first described by the German physiologist Emil DuBois-Reymond in 1849.However, it was not until over a century later that the underlying mechanism was explained in terms of the properties of the specific membrane proteins forming the voltage-gated ion channels of sodium and potassium ions. Second messenger system When receptors are directly linked to ion channels, fast excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs) occur. However, it is well established that slow potential changes also occur and that such changes are due to the receptor being linked to the ion channel indirectly via a second messenger system.For example, the stimulation of b- adrenoceptors by noradrenaline results in the activation of adenylate cyclase on the inner side of the nerve membrane. This enzyme catalyses the breakdown of ATP to the very labile, high-energy compound cyclic 3,5-adenosine monophosphate (cyclic AMP). Cyclic AMP then activates a protein kinase which, by phosphorylating specific membrane proteins, opens an ion channel to cause an efflux of potassium and an influx of sodium ions. Such receptors are termed metabotropic receptors.
Many monoamine neurotransmitters are now thought to work by this receptor-linked second messenger system. In some cases, however, stimulation of the postsynaptic receptors can cause the inhibition of adenylate cyclase activity. For example, D2 dopamine receptors inhibit, while D1 receptors stimulate, the activity of the cyclase. Such differences have been ascribed to the fact that the cyclase is linked to two distinct guanosine triphosphate (GTP) binding proteins in the cell membrane, termed GI and GS. The former protein inhibits the cyclase, possibly by reducing the effects of the GS protein which stimulates the cyclase.The possible role of the family of protein kinases which translate information from the second messenger to the membrane proteins. Many of these kinases are controlled by free calcium ions within the cell. It is now established that some serotonin (5-HT) receptors, for example, are linked via G proteins to the phosphatidyl inositol pathway which, by mobilizing membrane-bound diacylglycerol and free calcium ions, can activate a specific protein kinase C. This enzyme affects the concentration of calmodulin, a calcium sequestering protein that plays a key role in many intracellular processes. Structurally G-proteins are composed of three sub-units termed alpha, beta and gamma. Of these, the alpha sub-units are structurally diverse so that each member of the G-protein super-family has a unique alpha sub-unit. Thus the multiplicity of the alpha, and to a lesser extent the beta and gamma, sub-units provides for the coupling of a variety of receptors to different second messenger systems. In this way, different receptor types are able to interact and regulate each other, thereby allowing for greater signal divergence, convergence or filtering than could be achieved solely on the basis of the receptor diversity. The functional response of a nerve cell to a transmitter can change as a result of the receptor becoming sensitized or desensitized following a decrease or increase, respectively, in the concentration of the transmitter at the receptor site. Among those receptors that are directly coupled to ion channels, receptor desensitization is often rapid and pronounced.Most of the experime ntal evidence came initially from studies of the frog motor end-plate, where it was shown that the desensitization of the nicotinic receptor caused by continuous short pulses of acetylcholine was associated with a slow-conformational change in that the ion channel remained closed despite the fact that the transmitter was bound to the receptor surface.A similar mechanism has also been shown to occur in brain cells. For example, continuous exposure of b-adrenoceptors on rat glioma cells in vitro results in a rapid reduction in the responsiveness of the receptors. This is followed by a secondary stage of desensitization, whereby the number of b-receptors decreases. It seems likely that the receptors are not lost but move into the cell and are therefore no longer accessible to the transmitter.It must be emphasized that there is considerable integration and modulation between the various second messenger systems and these interactions lead to cross-talk between neurotransmitter systems. Such cross-talk between the second messenger systems may account for changes in the sensitivity of neurotransmitter receptors following prolonged
stimulation by an agonist whereby a reduction in the receptor density is associated with a reduced physiological response (also termed receptor down-regulation).
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