Neurotransmitter Receptors Case File

Neurotransmitter Receptors Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 9

A 65-year-old male presents to your office in the morning complaining of double vision and weakness with exertion. This has been ongoing for several months. He states that he feels best first thing in the morning. As the day progresses, however, he becomes more fatigued and will occasionally experience diplopia, or double vision. He has even felt too tired to make it through dinner. On physical examination, his extraocular movements are intact and he currently denies any double vision. He appears to have a mild ptosis. Muscle strength testing and muscle stretch reflexes are within normal limits. He has a narrow-based gait with appropriate arm swing. You notice that he is speaking progressively more softly and less clearly during the course of the examination. After some thought, you conclude that he has myasthenia gravis, a disorder of postsynaptic acetylcholine receptors (AChR).

• What are the two major types of neurotransmitter receptors?
• What type of receptor is involved at the neuromuscular junction in this case?
• What are possible treatments for this condition?

ANSWERS TO CASE 9: NEUROTRANSMITTER RECEPTORS

Summary: A 65-year-old male presents with double vision and progressive

fatigue over the course of the day.

• Receptors: The two types of neurotransmitters receptors are inotropic and metabotropic.
• Receptors involved in this case: The inotropic receptors at the neuromuscular junction.
• Treatments: Anticholinesterase medications, thymectomy, corticosteroids, immunosuppressive agents, plasma exchange, and intravenous immunoglobulin.

CLINICAL CORRELATION

Myasthenia gravis (MG) is predominantly an autoimmune disorder affecting the nicotinic AChR at the neuromuscular junction (NMJ), although a rarer, heritable form has also been described. MG is characterized by a fluctuating weakness which may vary over several minutes or days. The most commonly affected muscle groups include the levator palpebrae and the extraocular muscles, resulting in ptosis and diplopia. The muscles of mastication, facial expression, and speech can also be affected, resulting in dysphagia, expressionless faces, and dysarthria. It can also affect limb, abdominal, and respiratory muscles to varying degrees. MG has a prevalence estimated at around 40-80 per million of the population and an annual incidence of approximately 1 in 300,000 individuals. Tumors of the thymus gland are found in approximately 10%-15% of myasthenic patients, while fully 65% have evidence of lymphoid hyperplasia in the medulla of the thymus. Other autoimmune disorders, such as lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, and polymyositis, have also been associated with MG. In the autoimmune form, antibodies to the AChR are produced which interfere with synaptic transmission at the neuromuscular junction by several mechanisms. First, the antibodies act as a competitive antagonist of acetylcholine (ACh) at the NMJ. Second, there are fewer AChR at the NMJ in myasthenic patients. The anti-AChR antibodies also form cross-links with multiple AChR which results in the clustering of AChR, the internalization of the receptors by endocytosis, and, ultimately, the degradation of the AChR. Because of the reduced numbers of AChR and the competitive antagonism of ACh, the endplate potentials are not sufficient to generate action potentials in the muscle. This leads to the recruitment of fewer muscle fibers and the loss of overall contractile power in the muscle.

The diagnosis of MG is facilitated by several ancillary studies, including electromyography, a serum assay for anti-AChR antibodies, imaging of the chest to rule out the presence of a thymoma and edrophonium, and neostigmine tests which test motor strength before and after injection with either of the two anticholinesterase medications. These two drugs decrease the clearance of ACh at the NMJ and, in myasthenic patients, result in a marked improvement in strength following administration. There are several possible treatments for MG. Longer acting anticholinesterase drugs are often beneficial for patients afflicted with purely ocular myasthenia. If an enlarged thymus gland is detected, a thymectomy should be performed. Up to 80% of individuals younger than 55 years of age without a thymoma and who have had poor response to anticholinesterase medications also receive some benefit from thymectomy. Corticosteroids and immunosuppressive agents can also ameliorate the symptoms of MG.

APPROACH TO NEUROTRANSMITTER RECEPTORS

Objectives

1. Know that the two types of neurotransmitters are inotropic and metabotropic.
2. Describe how inotropic and metabotropic receptors function.
3. Describe the differences between G protein–coupled receptors and tyrosine kinase receptors.
4. Describe the differences between inotropic and metabotropic receptors.

Definitions

Inotropic receptors: Receptors that directly gate ion channels.

Metabotropic receptors: Receptors that rely on a variety of second messenger systems to indirectly gate ion channels.

G protein–coupled receptors: A type of metabotropic receptor that uses G proteins to activate various second messenger cascades.

Tyrosine kinase receptors: A type of metabotropic receptor that uses tyrosine kinases to phosphorylate proteins to initiate a second messenger pathway.

DISCUSSION

Neurotransmitter receptors are generally located on the postsynaptic membrane and have two important functions: to recognize and bind specific neurotransmitters and to alter the membrane potential of the postsynaptic cell. A single neurotransmitter can bind to several types of receptors, resulting in different effects at different synapses. There are two general classes of receptors: the inotropic and metabotropic receptors. Inotropic receptors have one or more binding sites for neurotransmitters which are directly coupled to iongated membrane channels. With binding of a specific neurotransmitter, the channel opens to allow passage of specific ions and alters the membrane potential. Metabotropic receptors are coupled to second messenger systems within the postsynaptic cell which also gate ion channels, albeit indirectly.

Inotropic receptors open with binding of the neurotransmitter and close with dissociation. The open channel allows for the passage of ions through the postsynaptic membrane and results in a brief, local postsynaptic potential (PSP). Unlike the action potential, the amplitude of the PSP varies depending on the amount of channels opened by the release of neurotransmitter.

One of the most prevalent neurotransmitter receptors is the ACh receptor. It is found throughout the autonomic nervous system and at the NMJ. Two types of AChR, nicotinic and muscarinic, have been identified. Nicotinic receptors are found in the NMJ and the preganglionic endings of both the sympathetic and parasympathetic nervous system. Muscarinic receptors are found in the postganglionic endings of all parasympathetic endings and in select sympathetic endings.

The nicotinic receptor is made up of five subunits; two alpha subunits, one beta, one gamma, and one delta subunit. The alpha subunits function as the extracellular binding site for the ACh molecules. The subunits form a channel which remains closed without ligand binding. The pore of the channel contains a ring of negatively charged molecules which select for positively charged ions. When two molecules of ACh bind to the alpha-subunits, the channel undergoes a conformational change and opens, allowing the passage of Na+ and K+ ions. Sodium ions flow into the cell and K+ ions flow out when the postsynaptic cell is at its resting membrane potential. This results in the depolarization of the postsynaptic cell. Certain GABA and glycine receptors also gate ion channels, but are selective for anions.

Glutamate has two different inotropic receptors: non-NMDA receptors which are permeable to Na+ and K+, and NMDA receptors which are permeable to K+, Na+, and Ca2+. NMDA receptors are normally blocked by an Mg2+ plug in the channel, and require both ligand binding of glutamate and depolarization to open. NMDA glutamate receptors are very important in longterm potentiation.

Metabotropic receptors gate ion channels through a different mechanism. The receptor is coupled to one of two second messenger systems, the G protein–coupled receptors and the tyrosine kinase receptors. The G protein–coupled receptor consists of a single subunit with seven transmembrane spanning regions. Binding of the neurotransmitter activates a GTPbinding protein which in turn activates one of several enzymes; adenylyl cyclase in the cyclic AMP pathway, phospholipase C in the IP3-DAG pathway, or phospholipase A2 in the arachidonic acid pathway. These enzymes trigger the second messenger cascade which ultimately results in the gating of an ion channel. Muscarinic AChR found in the CNS and autonomic parasympathetic system and adrenergic receptors found in the CNS and peripheral autonomic sympathetic system function through G protein–coupled systems.

Tyrosine kinase receptors consist of a single spanning protein, an extracellular receptor-binding domain and an intracellular protein kinase domain. Binding of the neurotransmitter to the extracellular site results in the dimerization of two receptors which activate the intracellular kinases. The kinase phosphorylates itself and other proteins on tyrosine residues. This leads to the activation of a second messenger cascade, which can alter gene transcription within the cell and can also modulate the activity of ion channels. These types of receptors are typically activated by neuropeptides and hormones.

There are several key functional differences between inotropic and metabotropic receptors. The action and duration of inotropic receptors are immediate, binding of a neurotransmitter results in the rapid opening of ion channels. The dissociation of the neurotransmitter closes the ion channel in a process that spans milliseconds. Metabotropic receptors act in a more delayed fashion because of their reliance on a series of reactions. The opening of the ion channel may take tens of milliseconds to seconds to occur and the duration may last from seconds to minutes.

Inotropic channels function to create either excitatory or inhibitory postsynaptic potentials in a well-localized area, the postsynaptic membrane. These potentials, when summed, can create or inhibit an action potential through its effect on neighboring voltage-gated ion channels. Metabotropic receptors are also excitatory or inhibitory, but work through freely diffusible second messenger systems which can interact with channels anywhere on the postsynaptic cell. The second messenger cascade can influence the activity of resting membrane channels, voltage-gated ion channels, or ligand-gated channels. Metabotropic receptors, unlike inotropic receptors, can not only open channels, but they can close them as well.

COMPREHENSION QUESTIONS

[9.1] A 67-year-old man presents to your clinic for management of his longstanding hypertension. He is currently taking atenolol (a norepinephrine β-receptor blocker) for management of his blood pressure. Which of the following processes is inhibited through use of this drug?

A. Opening of voltage-gated sodium and potassium channels

B. Opening of voltage-gated chloride channels

C. Stimulation of adenylate cyclase

D. Activation of phospholipase A2

[9.2] You are studying the behavior of a neuron to the application of neurotransmitter. Immediately following the application of neurotransmitter to the postsynaptic membrane you note a local alteration in the membrane potential. Several seconds later, however, the postsynaptic membrane behaves exactly as it did before the application of neurotransmitter. Through what mechanism is this neurotransmitter most likely to act?

A. Activation of adenylate cyclase

B. Activation of PLC

C. Activation of PLA2

D. Opening of a voltage-gated ion channel

[9.3] As part of a routine examination of a 27-year-old woman, you check her knee-jerk reflex. You tap her patellar tendon with your reflex hammer and her quadriceps muscle contracts appropriately. You recall that the motor nerve innervating the muscle releases ACh into the neuromuscular junction. What affect does this ACh release have on the postsynaptic muscle membrane?

A. Opening of ligand-gated sodium and chloride channels

B. Opening of ligand-gated sodium and potassium channels

C. Opening of ligand-gated potassium and chloride channels

D. Opening of ligand-gated sodium, potassium, and chloride channels

Answers

[9.1] C. Norepinephrine β-receptors activate adenylate cyclase via G proteins. Norepinephrine acts in the CNS and the PNS through activation of receptors that are G protein linked. There are a number of different receptors utilized by this neurotransmitter, and they fall into two broad categories, alpha and beta. α-Receptors in general are excitatory and are linked via the Gq second messenger to phospholipase C. β-Receptors tend to be inhibitory (although not always) and are linked via Gs or Gi to adenylate cyclase. Both answers A and B refer to inotropic receptors, which are involved in ACh neurotransmission and with amino acid neurotransmitters like glutamate and glycine. Phospholipase A2 is involved as a second messenger system in some neuropeptide neurotransmitters.

[9.2] D. The neuron described in this question appears to respond to neurotransmitter application via a voltage-gated ion channel. The effect of the neurotransmitter is immediate and local, and there appears to be no lasting effect on the neuron from its application. Any of the other mechanisms listed are G protein–coupled responses, which would take longer to have an effect, could potentially alter neuron physiology throughout the neuron, and have the potential to have a lasting effect on the neuron.

[9.3] B. The application of ACh to the neuromuscular junction results in the opening of ligand-gated sodium and potassium channels. The opening of these channels alter the permeability of the membrane to ions such that the membrane potential approaches zero, which is sufficiently depolarized to result in the opening of voltage-gated sodium channels. The opening of voltage-gated sodium channels triggers an action potential, resulting in muscular contraction.

NEUROSCIENCE PEARLS ❖ Neurotransmitters can bind two general classes of receptors: inotropic and metabotropic receptors. ❖ Inotropic receptors, when activated by a ligand, directly open a transmembrane ion-gated channel. ❖ Metabotropic receptors, when activated by a ligand, set off a cascade of intracellular molecular signals which then leads to an indirect opening of a transmembrane ion channel. ❖ Metabotropic receptors are coupled to either G protein–coupled receptors or tyrosine kinase receptors. ❖ ACh can bind to two types of AChR: nicotinic receptors and muscarinic receptors. ❖ Nicotinic receptors are found in the neuromuscular junction and the preganglionic endings of both the sympathetic and parasympathetic nervous system. ❖ Muscarinic receptors are found in the postganglionic endings of parasympathetic nervous system and in select sympathetic endings. ❖ NMDA receptors require both ligand binding of glutamate and depolarization to open, and are very important in long-term potentiation.

REFERENCES

Bear MF, Connors B, Paradiso M, eds. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 

Kandel E, Schwartz J, Jessell T, eds. Principles of Neural Science. 5th ed. New York: McGraw-Hill; 2000. 

Zigmond MJ, Squire LR, Bloom FE, Landis SC, Roberts JL. Fundamental Neuroscience. 2nd ed. San Diego, CA: Academic Press; 1999.

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