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 receptor, metabotrophic receptors, ligand gated ion channels, GABA gated channels, G protein, 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 neurotransmitter receptors at different stimuli. Understand the advantage of signal cascade mechanism. 2. Introduction Two adjacent neurons communicate with each other through specialized regions called as synapse. The communication between them occurs through the movement of chemical mediators called as neurotransmitters 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, dopamine 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 neuron. 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 ion channel 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 acetylcholine receptor 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