Paper : 06 Animal Physiology Module : 08 Receptors in neurotransmission

Development Team

Principal Investigator: Prof. Neeta Sehgal Department of Zoology, University of Delhi

Co-Principal Investigator: Prof. D.K. Singh Department of Zoology, University of Delhi

Paper Coordinator: Prof. Rakesh Kumar Seth Department of Zoology, University of Delhi

Content Writer: Dr. Kapinder and Dr Haren Ram Chiary Kirori Mal College, University of Delhi

Content Reviewer: Prof. Neeta Sehgal Department of Zoology, University of Delhi

Animal Physiology ZOOLOGY Receptors in neurotransmission

Description of Module

Subject Name ZOOLOGY

Paper Name Zool 006 Animal Physiology

Module Name/Title Receptors in neurotransmission

Module Id M 08 Receptors in neurotransmission

Keywords ionotropic , metabotrophic receptors, gated ion channels, GABA gated channels, , second messanger

Contents: 1. Learning outcomes 2. Introduction 3. Ionotropic receptors 3.1 Ligand-gated ion channels 3.1.1 Basic structure of ligand-gated ion channels 3.2 Glutamate-gated channels 3.3 GABA gated and glycine gated channels 4. Metabotropic receptors 4.1 G-protein-coupled receptors 4.2 Structure of G-protein receptors 4.3 The Ubiquitous G-proteins 4.4 G-protein-coupled effector systems 4.4.1 The shortcut pathway 5. Second messenger cascades 5.1 The advantage of signal cascades 6. Autoreceptors 7. Summary

Animal Physiology ZOOLOGY Receptors in neurotransmission

1. Learning Outcomes

After studying this module, you shall be able to:  Understand how nerve impulse travels from one axon to another axon.  Different types of receptors involved in neurotransmission.  Learn basic structure of Ionotropic and Metabotropic receptors.  Know mechanism of action of different receptors at different stimuli.  Understand the advantage of signal cascade mechanism.

2. Introduction

Two adjacent communicate with each other through specialized regions called as synapse. The communication between them occurs through the movement of chemical mediators called as across a small gap present between them. The neurotransmitter receptors are the proteins which functions as integral components during the communication of two adjacent neurons. These receptors are protruding into the cytoplasm of neurons and synaptic cleft. Activation of the neurons causes release of neurotransmitters from synaptic vesicles which are present in the pre-synaptic terminals. These neurotransmitters diffuse from pre-synaptic terminal to synaptic cleft and finally reach to the postsynaptic membrane. There are various types of neurotransmitters present in the neurons. Most of them are small hydrophilic molecules belongs to amino acids (l-glutamate, GABA and glycine), biogenic amines (serotonin, and nor-adrenaline) and low-molecular weight peptides (neurotensin and enkephalin) etc. These neurotransmitters are not able to cross the hydrophobic postsynaptic membrane of a . Therefore, they express their effect by interacting with the receptors located in the postsynaptic membrane of the adjacent neuron. Each neurotransmitter receptor has one or more neurotransmitter binding sites. Binding of a correct neurotransmitter to the receptor causes opening of an and forms a postsynaptic potential, either excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs) in the postsynaptic membrane of a cell. Neurotransmitter receptors can be categorized as ionotropic receptors or metabotropic receptors. This division

Animal Physiology ZOOLOGY Receptors in neurotransmission

is based on the fact that whether the binding site of neurotransmitter and the ion channel are part of same protein or are belongs to different proteins.

3. Ionotropic receptors

These are types of neurotransmitter receptor which consists of neurotransmitter binding site along with an ion channel as its integral component (figure 1). This type of receptor is also considered as a type of ligand-gated channel. In the absence of any ligand, the ion channel of these receptors remains closed. When neurotransmitter binds to these ionotropic receptors, it opens the ion channel which results in the postsynaptic EPSP or IPSP in the neuron.

Figure 1: Ionotropic receptors (Source: https://nanohub.org/app/site/courses/11/3234/slides/012.01.jpg

Several excitatory neurotransmitters when bind to the ionotropic receptors causes opening of cation channels that allow Na+, K+ and Ca2+ ions to pass through the postsynaptic membrane of a neuron. However, inflow of Na+ ion is more than Ca2+ inflow or K+ outflow, as a result, inside of the postsynaptic neuron becomes depolarized (less negative). Many inhibitory neurotransmitters when binds to ionotropic receptors having chloride channels, results in the opening of these Cl- channels and allow inward diffusion of larger number of chloride ions. The inward movement of these Cl- ions make inside of the postsynaptic cell to become hyperpolarized (more negative).

Animal Physiology ZOOLOGY Receptors in neurotransmission

3.1 Ligand-gated ion channels These are ionotropic receptors also known as ligand gated ion channels or transmitter gated ion channels are membrane-spanning proteins made up of 4 or 5 subunits that close together in such a manner to make a pore (figure 2). In absence of any neurotransmitter (ligand), the pore of the ion channel remains closed. When neurotransmitter attached to specific sites of ion channel, it brings some conformational change in the protein subunits within few microseconds and causes the opening of pore.

Figure 2: Ligand-gated ion channels

Ligand gated ion channels do not exhibit same degree of selectivity of ions as by the voltage- gated channels. At neuromuscular junction, acetylcholine-gated ion channels are permeable to sodium and potassium ions. When these open ion channels are permeable to Na+, they cause the membrane potential to reach the threshold and generate action potentials that depolarizes the postsynaptic cell. This effect is known to be excitatory. This depolarization of transient postsynaptic membrane caused by the pre-synaptic release of neurotransmitter is known as an excitatory postsynaptic potential (EPSP). For example, synaptic activation of Acetylcholine gated and glutamate-gated ion channels causes EPSPs. If these ligand-gated channels are permeable to chloride ions, it causes hyperpolarization of the postsynaptic cell. As it causes the membrane potential to move away from threshold for generating action potentials, this effect is known as inhibitory. The pre-synaptic release of neurotransmitter causes transient hyperpolarization of the postsynaptic membrane called as inhibitory postsynaptic potential (IPSP). For example, activation of synaptic GABA-gated or glycine-gated ion channels.

Animal Physiology ZOOLOGY Receptors in neurotransmission

3.1.1 Basic structure of ligand-gated ion channels The most deeply studied ligand-gated ion channel is the nicotinic

which admits both K+ and Na+. This receptor is best known for its role in synapses between motor neurons and skeletal muscle cells. A single ion channel can act as a sensitive detector of different chemicals and voltage and can also regulate the large currents flow with great precision and it can also select and filter similar ions that can be regulated by other receptor systems. The size of each channel in muscle plasma membranes is about 11 nm long which is opened by acetylcholine and causes the cation channel in the receptor to transmit 15,000 to 30,000 sodium or potassium ions in one millisecond. In the skeletal muscle, acetylcholine receptor is made up of pentameric protein subunits. It is arranged like the staves of a barrel to form a pore through the membrane. It consists of four different types of polypeptides designated as α, β, γ and δ. A pentameric unit is made from

two α subunits and one β, γ and δ each (designated as α2βγδ). The α, β, γ and δ subunits have considerable homology sequences in which about 35% to 40% of the residues are similar in any of the two subunits. Each molecule has about 9 nm diameter and out of which 2 nm of the molecule present into the cytosol and about 6 nm of it protrudes into the extracellular space. Each α subunits consists of one ACh binding site and simultaneous binding of ACh to both α subunits is necessary for opening the channel. The nicotinic ACh receptor on neurons is also a pentamer, however, unlike the muscle receptor, most of them are comprised of only

α and β subunits only (α3β2). Most of the other ligand-gated channels in the brain are also thought to be pentameric complexes having close similarities to the nicotinic ACh receptor. The most important exceptions are the glutamate-gated channels whose structure resembles that of potassium channels and this led to the hypothesis that both of these receptors are evolved from a common ancestral ion channel. The variations among ion channel structures are the ones that account for their differences. Different ligand binding sites causes one ion channel to respond to Glutamate whereas other responds to GABA; certain amino acids present at the narrow ion pore allow the flow of Na+

Animal Physiology ZOOLOGY Receptors in neurotransmission

and K+ through some channels, Cl- through other channels allow flow of Ca2+ through yet other channels. 3.2 Glutamate-gated channels In the mammalian brain, region of the hippocampus is associated with several types of short- term memory in which certain hippocampal neurons of postsynaptic cells receive inputs from many pre-synaptic neurons. In long-term potentiation, a burst of postsynaptic neuron stimulation makes it more responsive to succeeding stimulation by presynaptic neurons. For instance, when presynaptic nerve of hippocampal region is stimulated with 100 depolarizations that act over about 200 milliseconds is responsible for increasing the postsynaptic neuron sensitivity that can continues for few hours to several days. These changes in the postsynaptic responses may underlie certain types of memory. In the postsynaptic neurons, there are two types of glutamate-gated cation channels that participate in long-term potentiation (figure 3).

Figure 3: Glutamate-gated cation channels. Source:http://neurones.co.uk/Neurosciences/Images/1/0402-1- L%20NMDA%20receptors%20spines%207e.biopsychology.com%20%20.jpg

Three subtypes are AMPA receptors (힪-amino-3-hydroxy-5-methyl-4- isoxazole propionate), NMDA receptors (N-methyl-D-aspartate) and kainite receptors which mediate most of synaptic excitation in CNS. The NMDA-gated and AMPA gated channels mediate several fast excitatory synaptic transmission in the brain. Kainate receptors also present throughout the brain, however, their functions are not clearly understood.

Animal Physiology ZOOLOGY Receptors in neurotransmission

AMPA-gated ion channels are permeable to only Na+ and K+ ions but not to Ca2+. The activation of these channels at normal, negative membrane potentials allows diffusion of Na+ ions into the cell results in rapid and large depolarization. Hence, AMPA receptors mediate excitatory transmission at CNS synapses that is similar to nicotinic receptors which mediate synaptic excitation at neuromuscular junctions. In the brain AMPA receptors are present along with NMDA receptors at several synapses, therefore both receptors contribute to the components of most glutamate-mediated EPSPs (figure 3). NMDA-gated channels cause depolarization of a nerve cell by allowing diffusion of Na+; however, they differ in two ways from AMPA receptors: 2+ + 1) NMDA-gated channels allow entry of Ca ions and Na ions 2) Causes inward ionic current through NMDA-gated channels that is voltage dependent.

For opening of the glutamate ion channel, glutamate must be bound to the receptor and the membrane has to become partly depolarized. In this way, NMDA receptor acts as a coincidence detector; that is, it combines activity of the postsynaptic cell which is reflected in its depolarized plasma membrane as neurotransmitter is released from the pre-synaptic cell, generating a cellular response higher than effect caused by glutamate release alone. As postsynaptic cell becomes sensitized, it takes fewer action potentials in pre-synaptic neurons to induce postsynaptic depolarization. Calcium ions from pre-synaptic region elicit the release of neurotransmitter and post- synaptically it activates many enzymes as well as controls the opening of different channels. Excessive release of Ca2+ ions can also cause cell death. It occurs due to higher concentration of glutamate, which activates its different types of receptors and allow excessive flow of Na+, K+ and Ca2+ across the membrane and neural cell die due to over-excitation, a process called excitotoxicity. The NMDA subtype of the glutamate-gated channel play critical role in excitotoxicity because it allows the entry of Ca2+ ions. Neuron death occurs because of swelling of the cells due to excessive water uptake and stimulation of intracellular enzymes by Ca2+ ions which destroy lipids, proteins and nucleic acids. NMDA receptors opening is dependent on depolarization of membrane because at resting stage magnesium ions block the NMDA channel from the extracellular solution. A small depolarization of neuron membrane causes dissociation of Mg2+ ions from its receptor and

Animal Physiology ZOOLOGY Receptors in neurotransmission

therefore glutamate binding allows opening of the channel. The effect of Mg2+can be abolished by making a mutation of a single asparagine residue in the pore-lining of NMDA receptor that proves binding of Mg2+ ion in the channel. For the channel to pass the current, both glutamate binding and depolarization must coincide. Activation of one synapse even at high frequency can cause a small post synaptic depolarization of the cell membrane. The long-term potentiation (LTP) can be induced only when several synapses simultaneously stimulate single postsynaptic neuron. Hence, membrane depolarization requirement explains that LTP depends on the simultaneous activation of several synapses on the postsynaptic cell. 3.3 GABA gated and glycine gated channels In vertebrates, synaptic inhibition in the CNS is primarily mediated by γ-aminobutyric acid (GABA) and glycine. GABA is formed from glutamate by the loss of carboxyl group. In the human brain, GABA concentration is about 200 to 1000 times higher as compared to other neurotransmitters like acetylcholine, norepinephrine and dopamine. Glycine is considered as major inhibitory neurotransmitter in brain stem and spinal cord, whereas, GABA prevails its inhibitory effect elsewhere in the brain. Both GABA and glycine are responsible for activating the ligand-gated Cl- ion channels (figure 4 and 5).

Figure 4: GABA gated channel. Source: https://pubs.niaaa.nih.gov/publications/arh313/images/4_lov.gif

Animal Physiology ZOOLOGY Receptors in neurotransmission

Both inhibitory GABAA and glycine receptors have very similar structure as that of excitatory

nicotinic ACh receptors (figure 4 and 5). However, GABAA and glycine are selective for anions whereas, nicotine Ach receptor is selective for cations. Each receptor has 힪 subunits at which transmitter binds and 휷 subunits at which no transmitter binds.

Figure 5: Glycine gated channel. (Source: https://www.omicsonline.org/articles-images/molecular-genetic-medicine-Glycine-receptor- subunit-09-187-g006.png) The opening of chloride ion channels causes the membrane potential to shift towards Cl- equilibrium potential (E ), which is slightly more hyperpolarized as compare to resting Cl membrane potential (slightly negative) and therefore higher permeability of sodium ions will

be needed to depolarize the membrane. The permeability of GABA or glycine towards Cl- is induced very rapidly in a fraction of millisecond (msec), however, it lasts for a second or more. Therefore, glycine or GABA induces a quite long-lasting inhibitory postsynaptic response. Higher duration of synaptic inhibition can lead to coma and loss of consciousness whereas; very low duration of inhibition causes a spasm. Hence, it is more important to regulate

synaptic inhibition in the brain. Therefore, GABAA receptor has several sites other than its own site where chemicals can severely modulate its function. For example, two classes of

drugs, benzodiazepines and barbiturates bind to their site on the outside face of the GABAA channel. These drugs do not show any significant effect when they bind to the site in absence of GABA, However, in the presence of GABA, benzodiazepines increase the channel opening frequency whereas, barbiturates leads to increased channel openings duration. It

Animal Physiology ZOOLOGY Receptors in neurotransmission

results in more inhibitory Cl- current and higher IPSPs. These drugs are specific for the

GABAA receptor and do not have any effect on the function of glycine receptors. In addition to these drugs, ethanol also exhibit certain complex actions which include effects

on serotonin, nicotinic ACh, NMDA and glycine receptors. Effects of ethanol on GABAA channels depend on their specific structure. These numerous effect of drugs displays an

interesting paradox. As GABAA receptor did not evolve its modulatory binding sites of modern drugs for the benefit of human beings. Therefore, scientists started looking for endogenous ligands, natural chemicals that can bind to barbiturate and benzodiazepine sites

and function as inhibition regulators. One of such GABAA receptors modulators is neurosteroids which are metabolites of steroid . These neurosteroids are primarily synthesized in adrenal glands and gonads from cholesterol. In addition, it is also synthesized in glial cells of the brain. Some of the neurosteroids increase inhibitory function whereas, other represses inhibitory function and they seem to do so by binding to their own site on the

GABAA receptor, distinct from those of the above mentioned drugs.

4. Metabotropic receptors

These are neurotransmitter receptors that consists a neurotransmitter binding site but lack an ion channel as its integral part. However, these receptors are connected to a separate ion channel through a membrane protein known as G-protein (figure 6). The binding of a neurotransmitter to these receptors causes the G-protein to either directly open (or closes) the ion channel or indirectly by activating several other molecules such as “second messenger” in the cytosol that opens (or closes) the ion channels. Some inhibitory neurotransmitters are linked to K+ channels, which when bind to metabotropic receptors, causes opening of these K+ channels. The opening of K+ channels increases outward diffusion of larger number of potassium ions which causes hyperpolarization (more negative) inside of the postsynaptic cell.

Animal Physiology ZOOLOGY Receptors in neurotransmission

Figure 6: Metabotropic receptor. (Source: https://nanohub.org/app/site/courses/11/3234/slides/013.01.jpg)

The same neurotransmitter can function as excitatory at some synapses and inhibitory at other synapses. These excitatory or inhibitory functions of a neurotransmitter depend upon the structure of the receptor at which neurotransmitter binds. For instance, at some excitatory synapses, acetylcholine (ACh) binds to ionotropic receptors that generate EPSPs in the postsynaptic cell. Whereas, at some inhibitory synapses, acetylcholine binds to metabotropic receptors and subsequently generate IPSPs in the postsynaptic cell. 4.1 G-protein-coupled receptors There are several subtypes of G-protein-coupled receptors present in the neurotransmitter system. The transmission of nerve impulse at synaptic region is mediated by amine and amino acid neurotransmitters through binding on G-protein-coupled receptors. The action of neurotransmitter involves following steps: 1. Neurotransmitter binds to the neurotransmitter receptors which are embedded in the postsynaptic membrane. 2. The receptor activates G-proteins which freely move all along the intracellular face of the postsynaptic membrane. 3. The G-proteins activation triggers “effector” proteins that can be G-protein-gated ion channels or enzymes for synthesizing several second messengers. These second messengers activate additional cytosolic enzymes that regulate function of ion channels and can alter

Animal Physiology ZOOLOGY Receptors in neurotransmission

cellular metabolism. The G-protein-coupled receptors are also known as metabotropic receptors. However, one neurotransmitter exhibit different postsynaptic actions depending upon the type of receptors at which it binds. It can be explained by an example of Acetylcholine neurotransmitter binds on the heart and skeletal muscles. Acetylcholine decreases the rhythmic contractions of heart by slowing down hyperpolarization of the cardiac muscle fibers. Whereas, in the skeletal muscle, acetylcholine induces muscle contraction by increasing depolarization in the skeletal muscle. These different actions of same neurotransmitter can be explained by binding of these neurotransmitters at different receptors. In the heart muscle, a metabotropic ACh receptor is coupled by a G-protein to a potassium ion channel which when opens causes hyperpolarization of the cardiac muscle. In skeletal muscle, the receptor is ionotrophic, an ACh-gated ion channel is specifically permeable to sodium ions. The opening of these sodium ion channels depolarizes the skeletal muscle and causes muscle contraction. 4.2 Structure of G-protein receptors The structure of most of the G-protein-coupled receptors is simple and show deviations on a common plan. It consists of a single polypeptide having seven membrane-spanning alpha helices. Out of these, two extracellular loops of the polypeptide form transmitter binding sites (figure 7).

Figure 7: Structure of G-protein. (Source: http://nhsjs.com/wp-content/uploads/2010/02/gprotein.jpg)

Animal Physiology ZOOLOGY Receptors in neurotransmission

The structural variations in this loop will determine binding of different neurotransmitters, antagonists and agonists to the receptor. Two intracellular loops can bind to and activate G- proteins. The variation in the structure will determine which G-proteins and consequently, which effector systems will be activated in response to binding of the neurotransmitter. 4.3 The ubiquitous G-proteins G-proteins form common link in most of the signaling pathways that begins with a receptor and finish with effector proteins. There are several transmitter receptors as compared to G- proteins; therefore, some G-proteins can be activated by several receptors.

Figure 8: Functioning of G-protein. (Source: https://figures.boundless-cdn.com/18870/large/figure-09-01-05.jpeg)

G-proteins exhibit same basic mode of operation (Figure 8): 1. G-protein consists of three subunits, 힪, 휷 and 휸. During resting state, a GDP molecule is

attached to the G힪 subunit of G-protein and the entire complex floats on the inner membrane surface. 2. If GDP-bound G-protein strike into the suitable receptor which has a bound transmitter molecule, then G-protein exchange its GDP with GTP that it picks up from the cytosol.

Animal Physiology ZOOLOGY Receptors in neurotransmission

3. This activated G-protein bound with GTP, splits into two parts, the G힪 subunit having

GTP, and the G휷휸 complex. These split subunits move on to influence different effector proteins.

4. The G힪 subunit also behaves as an enzyme which subsequently breaks down GTP into

GDP. Therefore, G힪 ultimately terminates its own activity by breaking down the bound GTP into GDP.

5. After that, G힪 and G휷휸 subunits of G- proteins again come back and join together to start another cycle. It was found that some of the G-proteins exhibit the stimulating effect and other G-proteins could inhibit these same effectors. Thus, G-proteins can be subdivided as stimulatory G-

protein (GS) and inhibitory G-protein (Gi). 4.4 G-protein-coupled effector systems

When G-proteins get activated, they exhibit their effects either by binding to the G-protein- gated ion channels or G-protein-activated enzymes. As the first route does not consists of any other chemical intermediaries, sometimes it is also referred as shortcut pathway. 4.4.1 The shortcut pathway There are several neurotransmitters that use the shortcut pathway i.e. from receptor to G- protein and then to ion channel. One of the examples of shortcut pathway is cardiac muscarinic acetylcholine receptors that activate G-Protein. When neurotransmitter acetylcholine binds to the muscarinic acetylcholine receptors in heart muscle, it generates a slow inhibitory response. When cholinergic nerve in heart muscle is stimulated, it causes a long-lived hyperpolarization of the membrane which slows down the heart muscle contraction rate. The muscarinic acetylcholine receptor is a type of G-protein receptor which when activated leads to opening of K+ ion channels and subsequently causes hyperpolarization of plasma membrane. The muscarinic acetylcholine receptor consists of seven transmembrane α helices, binding of neurotransmitter to these receptor activates a trimeric transducing G-protein and + then the released G휷휸 subunit directly binds to and opens K channel. The potassium channels

opens immediately when G휷휸 subunit is added in the absence of acetylcholine. The cardiac muscarinic receptor explains the way in which G-protein coupled receptors affect ion

Animal Physiology ZOOLOGY Receptors in neurotransmission

channels where the active Gβγ subunit binds to the channel protein. Another example is

neuronal GABAB receptors coupled by potassium channels. The shortcut pathways are considered as fastest of G-protein-coupled systems but not as fast as transmitter-gated ion channel, which does not involve any intermediary between the receptor and channel. However, it is faster when compared to second messenger cascades. As G-protein diffuses within the membrane, so it cannot move very far, therefore it affects only nearby channels.

5. Second messenger cascades

G-proteins also have their effects by directly activating some enzymes that can trigger an elaborate series of biochemical reactions that ends in the activation of other “downstream” enzymes which can modify neuronal function. There are various second messengers which is present between the first enzyme till the last enzyme. This whole process that couples the neurotransmitter through multiple steps to activate downstream enzyme is known as second messenger cascade (Figure 9).

Figure 9: Second messenger cascade. (Source:https://classconnection.s3.amazonaws.com/248/flashcards/430248/jpg/pip2- calcium1314856691465.jpg)

The cAMP, a second messenger cascade is started with the activation of NE 휷 receptor that

activates stimulatory G-protein (GS). It further continues to stimulate adenylyl cyclase, a

Animal Physiology ZOOLOGY Receptors in neurotransmission

membrane-bound enzyme that converts ATP into cAMP. The subsequent increase in the level of cAMP in the cytosol activates a specific downstream enzyme, A (PKA). Most of the biochemical routes are regulated by a push-pull method in which one stimulates

and other inhibits them. The activation of a second type of NE receptor (힪2 receptor) leads to

the activation of inhibitory G-protein (Gi) that suppresses adenylyl cyclase activity and this effect can take primacy over the stimulatory system. Some messenger cascades can branch. For example, activation of various G-proteins can stimulate (PLC) enzyme that also floats in the membrane just like adenylyl cyclase. The

phospholipase C enzyme acts on a membrane phospholipid (PIP2 or phosphatidylinositol-4,5-

bisphosphate) and split it into two molecules named inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG) that acts as second messengers. DAG is a lipid-soluble molecule that remains within the plane of the membrane and activates a downstream enzyme called protein

kinase-C (PKC). Whereas, other molecule, IP3 is water soluble that moves away in the cytosol and binds to the specific receptors on SER (smooth endoplasmic reticulum) in the cell. These receptors are IP3-gated calcium channels that cause the organelles to release stored Ca2+ ions. Increased level of cytosolic Ca2+ can generate widespread and long-lasting effects. One of the effects is activation of an enzyme calcium-calmodulin-dependent protein kinase (CaMK) that is associated with the molecular mechanisms of memory. 5.1 The advantage of signal cascades The important advantage of signal cascade is the amplification of several ion channels. For example, activation of one G-protein-coupled receptor can cause several ion channels activation that occurs at several places in the cascade. When one neurotransmitter molecule bound to one receptor, it activates about 10–20 G-proteins. Each activated G-protein can further activate an enzyme adenylyl cyclase that generates several molecules of cAMP that can activate many kinases. Each activated kinase further phosphorylate several channels. If all components of the cascade were tied together in a clump, signaling would become very limited. The use of small messengers such as cAMP can diffuse very quickly and allows signaling at a distance over cell membrane. Signal cascades can also generate long-lasting chemical changes in cells, which may form the basis for a lifetime of memories.

Animal Physiology ZOOLOGY Receptors in neurotransmission

6. Autoreceptors

In addition to the postsynaptic density, the receptors of neurotransmitter are also located in the presynaptic terminal of axonal membrane. These pre-synaptic receptors are sensitive to neurotransmitter which are released by pre-synaptic terminal are considered as autoreceptors. Usually, these receptors are G-protein-coupled receptors that trigger the formation of second messengers. The activation of these receptors may exhibit different effect but the common known effect is the inhibition of release of neurotransmitters and in certain cases it also helps in the synthesis of neurotransmitter. Thus, it allows the regulation of presynaptic terminal by itself. These autoreceptors function like a safety valve which slows down the release of neurotransmitter when neurotransmitter concentration is high in the synaptic cleft.

7. Summary

 Neurotransmitters are not able to pass through the postsynaptic membrane. So, their effect can be expressed by interacting with receptors present in the postsynaptic membrane.  Neurotransmitter receptors can be categorized as ionotropic receptors or metabotropic receptors.  Ionotropic receptors contains a neurotransmitter binding site and an ion channel which are components of the same protein whereas, metabotropic receptors contains a neurotransmitter binding site but it does not have an ion channel as its integral part.  Ligand-gated ion channels are ionotropic receptors that are membrane-spanning proteins made up of 4 or 5 subunits that close together in such a manner to make a pore.  Deeply studied ligand-gated ion channel is the nicotinic acetylcholine receptor which

allows the entry of K+ and Na+ ions and involved in the synapses of motor neurons as well as skeletal muscle cell.

Animal Physiology ZOOLOGY Receptors in neurotransmission

 Most of the other ligand-gated channels in the brain are also thought to be pentameric complexes having close similarities to the nicotinic ACh receptor. The most important exceptions are the glutamate-gated channels whose structure resembles that of potassium channels.  There are different known subtypes of G-protein-coupled receptors whose transmitter action involves binding of neurotransmitter. The G-protein-coupled receptors are often referred as metabotropic receptors.  Several neurotransmitters are known to use the shortcut pathway such as cardiac muscarinic acetylcholine receptors that activate G-Proteins.  G-proteins also exhibit their effects by activating certain enzymes that can turn on a series of biochemical reactions to activate downstream enzyme is known as second messenger cascade such as cAMP.  The important advantage of signal cascade is the amplification of several ion channels. It can also produce chemical changes in the cell which are long-lasting and involved in a lifetime of memories.

Animal Physiology ZOOLOGY Receptors in neurotransmission