What is the general functional organization of a receptor? (page 11 of the "Neurochemistry" classnotes)

For a loose, practical analogy, think of the neuron as a computer with a touch-screen that contains a group of different software program icons. Your finger represents the neurotransmitter and each icon represents a different receptor. Depending upon which icon (receptor) your finger (neurotransmitter) contacts, a specific software program is initiated ( a functional change), which will carry out its own set of instructions and produce a particular result (a biological response). To make the analogy a bit more accurate, different computer touch-screens (neurons) would contain different combinations of software icons (receptors), and (I don't know how you would make this work) each of your fingers, representing different transmitters, would only be able to activate a specific set of icons (receptors).

In essence, membrane receptors represent a transmembrane signalling system of the neuron with an analogous function to that of sensory receptors on our bodies. In both cases, a signal from outside is converted into a different form of information inside. In the case of the body, an external physical stimulus impinging upon a sensory receptor is converted into action potentials within a particular neurosensory pathway. In the neuron, the binding of an exogenous chemical ligand with a membrane receptor activates a particular sequence of neurochemical changes within the neuron.

Here is a more concrete, scientific-sounding definition of a receptor: A receptor is a protein or protein complex, within the membrane, that has a binding site (or sites) that binds a neurotransmitter externally and has some kind of trans-membrane or intra-cellular domain that can signal that the transmitter is bound. The binding activates some kind of primary effector which produces some kind of change in the functional status of the neuron (e.g. opening of an ion channel, etc.) which leads to the biological response of the neuron (e.g. depolarization, hyperpolarization, etc.).

What are the major functional classes of receptors? (page 12 of the "Neurochemistry" classnotes)

There are two major functional classes of receptor: ionotropic and metabotropic.

An ionotropic receptor, when activated, directly affects the activity of a cell by directly opening ion channels (figure labeled A₁).

A metabotropic receptor influences the activity of a cell indirectly by first initiating a metabolic change in the cell. This metabolic change may ultimately affect the opening or closing of an ion channel or may alter some other activity of the cell such as protein transcription (figure labeled B₁).

What is the anatomical and functional organization of ionotropic and metabotropic receptors?

(page 13 of the "Neurochemistry" classnotes) The ionotropic receptor is actually a class of chemically-gated ion channel. The open or closed state of this class of chemically-gated channel is regulated by the binding of a neurotransmitter to an external domain on the ion channel. For ionotropic receptors, the receptor and primary effector are actually parts of the same macromolecule since the ion channel itself is the primary effector (the entity that initiates the change in the functional status of the neuron). In the figure, which represents the nicotinic acetylcholine receptor, the acetylcholine molecule binds to the receptor portion of the channel. Upon binding, the channel opens, changing the ionic permeability and hence changing the membrane potential.

(page 14 of the "Neurochemistry" classnotes) In contrast to the ion channel that comprises the ionotropic receptor, metabotropic receptors are comprised of a single membrane-spanning protein. An extracellular region of this protein has a high affinity for a neurotransmitter and functions as the binding site. When a neurotransmitter binds to the binding site of a metabotropic receptor, the receptor undergoes a configurational change that either directly or indirectly activates an enzyme. This enzyme, representing the primary effector, commonly catalyzes a change in the metabolism of the neuron by converting some substrate into an intracellular bioactive metabolite known as a second messenger. The extracellular first messenger, which is the neurotransmitter, has now led to production of an intracellular second messenger. The second messenger may in turn activate a secondary effector within the neuron that can carry out subsequent metabolic changes. Thus, the production of the second messenger is often the initial link in a chain of physiological alterations that ultimately lead to the biological response of the neuron.

The receptor on p.14 of the handout is an example of a G protein-coupled receptor, the most common category of metabotropic receptor in the nervous system.  For such receptors, activation of the primary effector enzyme is mediated by a membrane-bound G protein.  After the receptor binds transmitter, the receptor associates with the G protein which, in turn, activates the enzyme.

What are the major second messenger pathways?

We mentioned that metabotropic receptors employ intracellular second messengers in their operation. Although there are hundreds of metabotropic receptors, they operate using a fairly limited number of second messenger pathways. Only a few are well understood at this point. They are: 1) the cyclic AMP pathway, 2) the inositol triphosphate/diacylglycerol (IP3/DAG) pathway, and 3) the arachidonic acid pathway.

Figure A on page 15 of the handout shows the operation of one of these second messenger systems: the cyclic AMP pathway. When norepinephrine binds to the beta-adrenergic receptor, the membrane-bound enzyme adenylyl cyclase is activated. This activated enzyme then acts as the primary effector, converting the soluble substrate ATP into the second messenger cyclic-AMP. The soluble cyclic-AMP can diffuse within the cytoplasm and activate the secondary effector protein kinase A. Protein kinases are capable of phosphorylating elements of the neuron such as ion channels or regulators of protein transcription. This phosphorylation process changes the function of the ion channel or the regulator, thereby producing a change in membrane potential or protein transcription.

What are some major differences between ionotropic and metabotropic receptors with regard to their effects on neuron function?

Two major differences are latency and duration of action. Ionotropic receptors are often thought of as faster receptors than metabotropic receptors. Ionotropic receptors generally operate on a millisecond time frame since binding of transmitter directly alters the configuration of an ion channel.

Effects of metabotropic receptors are generally longer in onset and longer in duration. Since action involves production of second messengers and actions on secondary effectors, onset can take hundreds of milliseconds and actions can last seconds to minutes.

Another major difference is that the effects of ionotropic receptors are fairly localized while effects of metabotropic receptors are diffuse. The binding of transmitter with an ionotropic receptor simply alters an ion channel, whereas binding of transmitter with a metabotropic receptor often produces a soluble second messenger which can diffuse within the cytoplasm to affect a large spatial domain within the cell.

In addition, ionotropic receptors are usually associated with ion channel opening, whereas metabotropic receptors can lead to either ion channel opening or ion channel closing.

Three final points to remember about receptors:

There is usually more than one receptor for a given neurotransmitter in the nervous system and these receptors often mediate different effects. For example, there are at least 15 different serotonin receptors, some cause depolarization and some cause hyperpolarization. A given neuron will often possess receptors for more than one neurotransmitter.

The function of a neurotransmitter is not an inherent property of the transmitter itself, but is defined by the receptors which it activates. In other words, glutamate can cause a post-synaptic depolarization because it activates a receptor which leads to depolarization. Serotonin can cause depolarization at some synapses and hyperpolarization at others because it respectively activates different types of serotonin receptors at those synapses.

Receptors are not confined to cell bodies and dendrites. They can exist on axon terminals as well. In fact, there are some receptors at the bouton called autoreceptors that are activated by the transmitter released from that bouton. This can act as sort of a negative feedback system for transmitter release.

Clinical significance

Receptors can be targets for the action of animal toxins and for disease. They are also an important means for the pharmacological control of nervous system function (both therapeutic and illicit). The snake venom alpha-bungarotoxin can block the acetylcholine binding site on the nicotinic acetylcholine receptor, preventing its activation by acetylcholine. Since these excitatory receptors are found on skeletal muscle, alpha-bungarotoxin can produce muscle paralysis. Myasthenia gravis is an autoimmune disorder that attacks the nicotinic acetylcholine receptor, leading to its destruction and resulting in severe muscle weakness. The benzodiazepines, such as Xanax, are anti-anxiety drugs. They bind to the GABA-A receptor, which is a chemically-gated chloride channel and can increase the amount of time chloride ions flow through the channel. This leads to extended hyperpolarization of the neuron and a decreased probability of generating an action potential.

Animations

To see some nice animations that illustrate the difference between ionotropic and metabotropic receptors, click on the link below, or enter the URL in your browser at a later time.

http://www.blackpublishing.com/matthews/neurotrans.html

When you're at the site, click on the button for "Direct neurotransmitter action". This shows an example of the operation of an ionotropic receptor. In this case, it is a nicotinic acetylcholine receptor on skeletal muscle, but it works in a similar fashion in neurons. The binding of acetylcholine to the receptor molecule, which in the case of ionotropic receptors is the ion channel itself, leads to direct opening of the channel and subsequent change in the membrane potential.

If you click on the button for "Norepinephrine promotes the activation of voltage-dependent calcium channels in cardiac-muscle cells", you will see an example of the operation of a metabotropic receptor. In this case, it is a beta-adrenergic receptor. Norepinephrine binds to the receptor protein, which is a single protein molecule threaded through the membrane. This leads to indirect activation of the enzyme adenylyl cyclase, which is embedded in the membrane and which acts as the primary effector. The activation of the enzyme results in the production of the second messenger cyclic AMP (cAMP). The cAMP second messenger then activates a secondary effector, in this case, cAMP-dependent protein kinase, which phosphorylates a voltage-gated calcium channel. This process of phosphorylation is the downstream endpoint of the metabolic change originally initiated by the primary effector, which is the adenylyl cyclase enzyme. Phosphorylation of the channel alters the function of the voltage-gated calcium channel so that when it opens upon depolarization of the membrane, it opens faster and stays opened longer.