Actions ofAcetylcholine and Norepinephrine on Cardiac Muscle Cells

Each muscle fiber of a skeletal muscle receives a direct synaptic input from a particular motor neuron; without this synaptic input, a skeletal fiber does not contract unless stimulated directly by artificial means. Nevertheless, we have seen that cardiac muscle fibers generate spontaneous contractions that are coordinated into a functional heartbeat by the electrical conduction mechanisms inherent in the heart itself. This does not mean, however, that the activity of the heart is not influenced by inputs from the nervous system. The heart receives two opposing neural inputs that affect the heart rate. One input comes from the cells of the parasympathetic nervous system, whose synaptic terminals in the heart release the neurotransmitter ACh. The effect of ACh is to slow the rate of depolarization during the pacemaker potential of the SA node. This has the effect of increasing the interval between successive action potentials and thus slowing the rate at which this master pacemaker region drives the heartbeat. Acetylcholine acts by increasing the potassium permeability of the muscle fiber membrane. This tends to keep the membrane potential closer to the potassium equilibrium potential and thus retard the growth of the pacemaker potential toward threshold for triggering an action potential. The second neural input to the heart comes from neurons of the sympathetic nervous system, whose synaptic terminals release the neurotransmitter nore-pinephrine. Activation of this input speeds the heart rate and also increases the strength of contraction. This effect is mediated via an increase in the calcium permeability that is activated upon depolarization. Thus, the parasympathetic and sympathetic divisions of the autonomic nervous system have opposite effects on the heart,just as they typically do in all other target organs as well.

Both the effect of ACh on potassium channels and the effect of nore-pinephrine on calcium channels are indirect effects. Recall from Chapter 9 that neurotransmitters can affect ion channels either directly (as is the case for ACh at the neuromuscular junction) or indirectly via intracellular second messengers. In the heart, the ACh released by the parasympathetic neurons binds to and activates a type of ACh receptor quite different from the nonspecific cation channel that is directly activated by ACh at the neuromuscular junction. This type of receptor is called the muscarinic acetylcholine receptor (because it is activated by the drug muscarine and related compounds, as well as by ACh). The ACh receptor at the neuromuscular junction is called the nicotinic acetylcholine receptor (because it is activated by the drug nicotine and related compounds). Muscarinic receptors are not themselves ion channels. Instead, the activated receptor binds to and stimulates GTP-binding proteins (G-proteins, see Chapter 9) that are attached to the inner surface of the membrane near the receptors. This sequence is diagrammed in Figure 12-9. In their active form, with GTP bound, the G-proteins then cause potassium channels to open, increasing the potassium permeability of the muscle cell and slowing the rate of action potentials. The effect of the G-proteins on the channel may be direct, by binding of the channel protein to one or more subunits of the active G-protein, or it may be indirect by stimulation of arachidonic acid, a second messenger produced by enzymatic cleavage of membrane lipids. The muscarinic receptor activates the G-protein by inducing the replacement ofGDP by GTP at the GTP binding site. The G-protein remains active interacting with and opening potassium channels as long as GTP occupies the binding site on the G-protein. The activity of the G-protein is terminated by the intrinsic GTPase activity of the G-protein itself, which ultimately hydrolyzes the terminal phosphate of the GTP, converting it to the inactive GDP.

The linkage between the norepinephrine receptor of the cardiac muscle cells and the calcium channels is also mediated via G-proteins. This is summarized in Figure 12-10. The receptor on the cell surface that detects nor-epinephrine is a type called the P-adrenergic receptor (there is also a different

Figure 12-9 Acetylcholine indirectly opens potassium channels in cardiac muscle cells. The synaptic terminals of parasympathetic neurons release ACh, which binds to muscarinic ACh receptor molecules in the membrane of the postsynaptic muscle cell. The receptor then activates G-proteins, by catalyzing the replacement of GDP by GTP on the GTP-binding site on the a-subunit of the G-protein. The b- and y-subunits dissociate from the a-subunit when GTP binds. The potassium channel is thought to open when the b- and y-subunits directly interact with the channel. (Animation available at www.blackwellscience.com)

Figure 12-9 Acetylcholine indirectly opens potassium channels in cardiac muscle cells. The synaptic terminals of parasympathetic neurons release ACh, which binds to muscarinic ACh receptor molecules in the membrane of the postsynaptic muscle cell. The receptor then activates G-proteins, by catalyzing the replacement of GDP by GTP on the GTP-binding site on the a-subunit of the G-protein. The b- and y-subunits dissociate from the a-subunit when GTP binds. The potassium channel is thought to open when the b- and y-subunits directly interact with the channel. (Animation available at www.blackwellscience.com)

class of norepinephrine receptor called the a-adrenergic receptor, but that class is not involved in the effects of norepinephrine we are discussing here). P-Adrenergic receptors are members of the same family of receptors as the muscarinic cholinergic receptors we discussed above. Like the muscarinic

Sympathetic nerve terminal

Sympathetic nerve terminal

Voltage-dependent calcium channel

Plasma membrane nside

Cardiac muscle cell cAMP-dependent protein kinase (protein kinase A)

Figure 12-10 Norepinephrine promotes the activation of voltage-dependent calcium channels in cardiac muscle cells. When norepinephrine is released from the synaptic terminals of sympathetic neurons, it combines with b-adrenergic receptors in the postsynaptic membrane of the cardiac muscle cells. The activated receptor stimulates G-proteins, by catalyzing binding of GTP to the a-subunit, which then dissociates from the b- and y-subunits. The a-subunit of the G-protein activates adenylyl cyclase, an enzyme that converts ATP into cyclic AMP. Cyclic AMP then stimulates protein kinase A, which phosphorylates calcium channel molecules. Phosphorylated calcium channels open more readily during depolarization and also remain open for a longer time. As a result, calcium influx increases during depolarization of the heart cell. (Animation available at www.blackwellscience.com)

Voltage-dependent calcium channel

Outside

Plasma membrane nside

Cardiac muscle cell cAMP-dependent protein kinase (protein kinase A)

Figure 12-10 Norepinephrine promotes the activation of voltage-dependent calcium channels in cardiac muscle cells. When norepinephrine is released from the synaptic terminals of sympathetic neurons, it combines with b-adrenergic receptors in the postsynaptic membrane of the cardiac muscle cells. The activated receptor stimulates G-proteins, by catalyzing binding of GTP to the a-subunit, which then dissociates from the b- and y-subunits. The a-subunit of the G-protein activates adenylyl cyclase, an enzyme that converts ATP into cyclic AMP. Cyclic AMP then stimulates protein kinase A, which phosphorylates calcium channel molecules. Phosphorylated calcium channels open more readily during depolarization and also remain open for a longer time. As a result, calcium influx increases during depolarization of the heart cell. (Animation available at www.blackwellscience.com)

receptor, the P-adrenergic receptor is not itself an ion channel. The receptor activates G-proteins inside the cell when norepinephrine occupies its binding site on the outside of the cell. In this case in the heart, the G-protein is a member of a class that exerts its cellular actions by changing the level of cyclic AMP inside the cell. The synthetic enzyme for cyclic AMP, adenylyl cyclase, is activated by the G-protein, causing cyclic AMP levels to rise inside the cardiac cell. Cyclic AMP binds to and stimulates protein kinase A (also called cyclic-AMP-dependent protein kinase), which in turn attaches a phosphate group to (phosphorylates) specific amino-acid groups of the calcium channel protein. Phosphorylation of the calcium channel is thought to be required for the channel to be able to open in response to depolarization, so an increase in cyclic AMP inside the cell translates into a greater number of openable calcium channels in the cell. In addition, each channel remains open for a longer time, on average, when it opens. Thus, phosphorylation of the channels greatly potentiates the inward calcium current that flows when the cardiac muscle cells are depolarized.

In the SA node, the triggering of the action potential depends on calcium channels. If there are more calcium channels available, the threshold potential for triggering the action potential will be lower and so the action potential will be triggered earlier during the pacemaker potential in the presence of nor-epinephrine. Outside of the SA node, in the muscle cells of the atria and ventricles, the role of the calcium channels is to produce the plateau phase of the action potential and to allow calcium influx, which contributes to the muscle contraction. An increase in the number of available calcium channels in these cells will increase the calcium influx during the plateau and thus increase the strength of contraction of the overall heart muscle. The combination of the increase in heart rate and the increase in strength of contraction makes the P-adrenergic receptors a powerful regulator of the amount of blood volume circulated per minute through the heart. The P-adrenergic receptors which ultimately exert their effect by increasing the phosphorylation of voltage-activated calcium channels are therefore targeted by many drugs that are used clinically to increase the heart output in human patients whose heart muscle has been damaged by disease.

One advantage of having the autonomic neurotransmitters exert their actions through G-protein-linked receptors, rather than by direct binding to ion channels, is that the nervous system can produce rather long-term effects on the ion channels of the heart without having to continuously provide an ongoing neural signal. Once the G-proteins are activated, they can affect channel activity for several seconds, until their activation terminates when GTP is hydrolyzed by the G-protein. Thus, ACh can be released briefly from parasympathetic nerve terminals (or norepinephrine from sympathetic nerve terminals) and still affect the heart rate for several seconds after the ACh stops being released. If instead, ACh bound to and opened a ligand-gated potassium channel in order to increase potassium permeability, the neurotransmitter would have to be continuously present, requiring the nervous system to continuously send signals from the central nervous system to the autonomic ganglia to produce a steady train of action potentials in the autonomic motor neurons. In the somatic nervous system, this is exactly what happens. Somatic motor neurons are tightly temporally coupled to the activation of their targets, the skeletal muscle fibers. This allows rapid, sub-second turn-on and turn-off of muscle activity under the control ofthe somatic nervous system. In general, the targets controlled by the autonomic nervous system are involved in much slower activities that are typically sustained for longer periods. Therefore, the slower and more sustained activation produced by indirect linkage between neuro-transmitter receptor and ion channels seems well suited for the autonomic nervous system.

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