Chemical Signaling by Neurotransmitters and Hormones – Neurotransmitter Receptors and Second-Messenger Systems

There are two major families of neurotransmitter receptors

In a previously post, you were introduced to the concept of a drug receptor. Many of the receptors for psychoactive drugs are actually receptors for various neurotransmitters. For this reason, it is very important to understand the characteristics of neurotransmitter receptors and how they function.

Virtually all neurotransmitter receptors are proteins, and in most cases these proteins are located on the plasma membrane of the cell. As we saw earlier, the cell possessing the receptor may be a neuron, a muscle cell, or a secretory cell. The neurotransmitter molecule binds to a specific site on the receptor molecule, which activates the receptor and produces a biochemical alteration in the receiving cell that may affect its excitability. For example, postsynaptic receptors on neurons usually influence the likelihood that the cell will generate an action potential. The effect of receptor activation may either be excitatory (increasing the probability of an action potential) or inhibitory (decreasing the probability of an action potential), depending on what the receptor does to the cell (see following sections). Recall that if a particular drug mimics the action of the neurotransmitter in activating the receptor, we say that the drug is an agonist at that receptor. If a drug blocks or inhibits the ability of the neurotransmitter to activate the receptor, then the drug is called an antagonist.

Two key concepts are necessary for understanding neurotransmitter receptors. First, almost all neurotransmitters discovered so far have more than one kind of receptor. Different varieties of receptors for the same transmitter are called receptor subtypes for that transmitter. The existence of subtypes adds complexity to the study of receptors, making the task of pharmacologists (as well as students!) more difficult. But this complexity has a positive aspect: If you can design a drug that stimulates or blocks just the subtype that you’re interested in, you may be able to treat a disease more effectively and with fewer side effects. That is one of the central ideas that underlies modern drug design and the continuing search for new pharmaceutical agents.

The second key concept is that most neurotransmitter receptors fall into two broad categories: ionotropic receptors and metabotropic receptors. A particular transmitter may only use receptors that fit one or the other of these general categories, or its receptor subtypes may fall into both categories. Ionotropic and metabotropic receptors differ in both their structure and function, so we will discuss them separately.

lonotropic receptors Ionotropic receptors work very rapidly, so they play a critical role in fast neurotransmission within the nervous system. Each ionotropic receptor is made up of several proteins called subunits, which come together in the cell membrane to form the complete receptor. Either four or five subunits are needed, depending on the receptor’s overall structure. At the center of the receptor is a channel or pore through which ions can flow. The receptor also possesses one or more binding sites for the neurotransmitter. In the resting state with no neurotransmitter present, the receptor channel is closed and no ions are moving. When the neurotransmitter binds to the receptor and activates it, the channel immediately opens and ions flow across the cell membrane. When the neurotransmitter molecule leaves (dissociates from) the receptor, the channel quickly closes. Because of these features, a common alternative name for ionotropic receptors is ligandgated channel receptors.

Some ionotropic receptor channels allow sodium (Na+) ions to flow into the cell from the extracellular fluid. Since these ions are positively charged, the cell membrane is depolarized, thereby producing an excitatory response of the postsynaptic cell. The best-known example of this kind of excitatory ionotropic receptor is the nicotinic receptor for ACh. A second type of ionotropic receptor channel permits the flow of Ca2+ as well as Na+ ions across the cell membrane. As we will see shortly, Ca2+ can act as a second messenger to trigger many bio-chemical processes in the postsynaptic cell. One important ionotropic receptor that functions in this way is the N- methyl-D-aspartate (NMDA) receptor for the neurotransmitter glutamate. Finally, a third type of receptor channel is selective for chloride (Cl-) ions to flow into the cell. These ions are negatively charged, thus leading to a hyperpolarization of the membrane and an inhibitory response of the postsynaptic cell. A good example of this kind of inhibitory ionotropic receptor is the GABAa receptor. From this discussion, you can see that the characteristics of the ion channel controlled by an ionotropic receptor are the key factor in determining whether that receptor excites the postsynaptic cell, inhibits the cell, or activates a second-messenger system.

Metabotropic receptors Metabotropic receptors act more slowly than ionotropic receptors. It takes longer for the post-synaptic cell to respond, but the response is also somewhat more long-lasting than in the case of ionotropic receptors. Metabotropic receptors comprise only a single protein subunit, which winds its way back and forth through the cell membrane seven times. Using the terminology of cell biology, we say that these receptors have seven transmembrane domains; in fact, they are sometimes abbreviated 7-TM receptors. It is important to note that metabotropic receptors do not possess a channel or pore. How, then, do these receptors work?

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Metabotropic receptors work by activating other proteins in the cell membrane called G proteins. Consequently, another name for this receptor family is G protein-coupled receptors. There are many different kinds of G proteins, and how a metabotropic receptor influences the postsynaptic cell depends on which G protein(s) the receptor activates. However, all G proteins operate by two major mechanisms. One is by stimulating or inhibiting the opening of ion channels in the cell membrane. Potassium (K+) channels, for example, are stimulated by specific G proteins at many synapses. When these channels open, K+ ions flow out of the cell, the membrane is hyperpolarized, and consequently the cell firing is suppressed. This is a common mechanism of synaptic inhibition used by various receptors for ACh, DA, NE, 5-HT, GABA, and some neuropeptides like the endorphins. Note that the K+ channels controlled by G proteins are not the same as the voltage-gated K+ channels that work together with voltage-gated Na+ channels to produce action potentials.

The second mechanism by which metabotropic receptors and G proteins operate is by stimulating or inhibiting certain enzymes in the cell membrane. These enzymes are sometimes called effector enzymes because they produce biochemical and physiological effects in the postsynaptic cell.

Most of the effector enzymes controlled by G proteins are involved in either the synthesis or breakdown of small molecules called second messengers. Second messengers were first discovered in the 1960s and later found to play an important role in the chemical communication processes of both neurotransmitters and hormones. In these processes, the neurotransmitter or hormone was considered to be the “first messenger,” and the “second messenger” within the receiving cell (the postsynaptic cell, in the case of a neurotransmitter) then carried out the biochemical change signaled by the first messenger. Putting everything together, this mechanism of metabotropic receptor function involves (1) activation of a G protein, followed by (2) stimulation or inhibition of an effector enzyme in the membrane of the postsynaptic cell, followed by (3) increased synthesis or breakdown of a second messenger, followed by (4) biochemical or physiological changes in the postsynaptic cell due to the altered levels of the second messenger. This sequence of events is an example of a biochemical “cascade.”

Second messengers work by activating specific protein kinases in a cell

Second-messenger systems are too complex to be completely covered in this text. We will therefore highlight a few of the most important systems and how they alter cellular function. One of the key ways in which second messengers work is by activating enzymes called protein kinases. Kinases are enzymes that phosphorylate another molecule; that is, they catalyze the addition of one or more phosphate groups (—P042-) to the molecule. As the name suggests, a protein kinase phosphorylates a protein. The substrate protein might be an ion channel, an enzyme involved in neurotransmitter synthesis, a neurotransmitter receptor or transporter, a structural protein, or almost any other kind of protein. The phosphate group(s) added by the kinase then alters the functioning of the protein in some way. For example, an ion channel might open, a neurotransmitter-synthesizing enzyme might be activated, a receptor might become more sensitive to the neurotransmitter, and so forth. Furthermore, kinases can phosphorylate proteins in the cell nucleus that turn on or turn off specific genes in that cell. You can see that protein kinases activated by second messengers are capable of producing widespread and profound changes in the postsynaptic cell, even including long-lasting changes in gene expression.

Now let us consider a few specific second messengers and their protein kinases. The first second messenger to be discovered was cyclic adenosine monophosphate (cAMP). Levels of cAMP are controlled by receptors for a number of different neurotransmitters, including DA, NE, 5-FIT, and endorphins. Cyclic AMP stimulates a protein kinase called protein kinase A (PKA). A related second messenger is cyclic guanosine monophosphate (cGMP). One of the key regulators of cGMP is the novel gaseous messenger nitric oxide. Cyclic GMP has its own kinase known as protein kinase G (PKG). A third second-messenger system is sometimes termed the phosphoinositide second-messenger sys-tem. This complex system has several different effects, including activation of protein kinase C (PKC) and elevation of the level of Ca2+ ions within the postsynaptic cell. The phosphoinositide system is controlled by receptors for several neurotransmitters, including ACh, NE, and 5-HT. Finally, Ca2+ itself is a second messenger. Calcium levels in the cell can be increased by a number of different mechanisms, including the phosphoinositide second-messenger system, voltage-sensitive Ca2+ channels, and, as mentioned earlier, certain ionotropic receptors like the NMDA receptor. The protein kinase activated by Ca2+ requires the participation of an additional protein known as calmodulin. Hence, it is called calcium/calmodulin kinase (CaMK). Ca2+ also helps to activate PKC.

Tyrosine kinase receptors mediate the effects of neurotrophic factors

There is one more family of receptors that you need to learn about, the tyrosine kinase receptors. These receptors mediate the action of neurotrophic factors, proteins that stimulate the survival and growth of neurons during early development and are also involved in neuronal signaling. Nerve growth factor (NGF) was the first neurotrophic factor to be discovered, but there are now known to be many others, including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4.

Three specific tyrosine kinase receptors are used by these neurotrophic factors: trkA (pronounced “track A”) for NGF, trkB for BDNF and NT-4, and trkC for NT-3. The trk receptors are activated through the following mechanism. After the neurotrophic factor binds to its receptor, two of these complexes come together in the cell membrane, a process that is necessary for receptor activation. When the two trk receptors are activated, they phosphorylate each other on tyrosine residues’*’ (hence the “tyrosine kinase receptor”) located within the cytoplasmic region of each receptor. This process then triggers a complex sequence involving additional protein kinases, including some that differ from those described in the previous section. Tyrosine kinase receptors and the neurotrophic factors they serve generally participate more in regulating long-term changes in gene expression and neuronal functioning than in rapid synaptic events that determine the rate of cell firing.

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