Lecture 3 Synapses - Biological Psychology 1 - PSY1617

PSY1617 BILOGICAL PSYCHOLOGY 1 Synapses Dr Massimo Pierucci  Summary of the lecture Concept of synapse Types of synapse Structure and Physiology of synapses Neurotrasmitters Various classes of neurotransmitters Ionotropic/Metabotropic receptors Differences in...

PSY1617 BILOGICAL PSYCHOLOGY 1 Synapses Dr Massimo Pierucci  Summary of the lecture Concept of synapse Types of synapse Structure and Physiology of synapses Neurotrasmitters Various classes of neurotransmitters Ionotropic/Metabotropic receptors Differences in structure and signal transduction  The Concept of the Synapse Neurons communicate by transmitting chemicals at junctions, called “synapses” – The term was coined by Charles Scott Sherrington in 1906 to describe the specialized gap that existed between neurons – Sherrington’s discovery was a major feat of scientific reasoning  A century ago, Cajal hypothesized that sites of contact between nerve cells, later termed synapses, were fundamental in the processing of information by the brain. © Cengage Learning 2016 Sherrington gave the first functional evidence of the presence of gaps between neurons Sherrington inferred: the existence of a specialized gap between neurons from synaptic delay – The Synapse spatial/temporal summation properties the excitatory and inhibitory nature of the synapses – Investigated how neurons communicate with each other by studying reflexes (automatic muscular responses to stimuli) in a process known as a reflex arc (leg flexion reflex)  5 ELEMENTS OF A NERVOUS REFLEX 1.Sensory receptors 2.Afferent neural pathways 3.Control centers in the CNS 4.Efferent neural pathways 5.Effectors 6 © Cengage Learning 2016 The Relationship Among a Sensory Neuron, Intrinsic Neuron, and Motor Neuron Antagonistic muscles 2 3 1 4 5 Three Important Points About Reflexes Sherrington’s observations – Reflexes are slower than conduction along an axon – Several weak stimuli present at slightly different times or slightly different locations produce a stronger reflex than a single stimulus – As one set of muscles becomes excited, another set relaxes Difference in the Speed of Conduction Sherrington found a difference in the speed of conduction in a reflex arc from previously measured action potentials – He believed the difference must be accounted for by the time it took for communication between neurons – Evidence validated the idea of the synapse Sherrington’s Evidence for Synaptic Delay  Temporal Summation Sherrington observed that repeated stimuli over a short period of time produced a stronger response Thus, the idea of temporal summation – Repeated stimuli can have a cumulative effect and can produce a nerve impulse when a single stimuli is too weak  Spatial Summation, Part 1 Sherrington also noticed that several small stimuli in a similar location produced a reflex when a single stimuli did not Thus, idea of spatial summation – Synaptic input from several locations can have a cumulative effect and trigger a nerve impulse  Spatial Summation, Part 2 Spatial summation is critical to brain functioning Each neuron receives many incoming axons that frequently produce synchronized responses Temporal summation and spatial summation ordinarily occur together The order of a series of axons influences the results Temporal and Spatial Summation The Effects of Summation Excitatory Postsynaptic Potential (EPSP) Presynaptic neuron: neuron that delivers the synaptic transmission Postsynaptic neuron: neuron that receives the message Excitatory postsynaptic potential (EPSP): graded potential that decays over time and space The cumulative effect of EPSPs are the basis for temporal and spatial summation Recordings From a Postsynaptic Neuron During Synaptic Activation John Eccles (1964) © Cengage Learning 2016 Antagonistic Muscles  Inhibitory Synapses Sherrington noticed that during the reflex that occurred, the leg of a dog that was pinched retracted while the other three legs were extended – Suggested that an interneuron in the spinal cord sent an excitatory message to the flexor muscles of one leg and an inhibitory message was sent to the other three legs Inhibitory Postsynaptic Potential (ISPS) Thus, the idea of inhibitory postsynaptic potential (ISPS) – the temporary hyperpolarization of a membrane – Occurs when synaptic input selectively opens the gates for positively charged potassium ions to leave the cell, or negatively charged chloride ions to enter the cells – Serves as an active “brake” that suppresses excitation Sherrington’s Inference of Inhibitory Synapses A Possible Wiring Diagram for Synapses  Spontaneous Firing Rate The periodic production of action potentials despite synaptic input – EPSPs increase the number of action potentials above the spontaneous firing rate – IPSPs decrease the number of action potentials below the spontaneous firing rate  Varieties of synapses © Cengage Learning 2016  Relationship Among EPSP, IPSP, and Action Potentials Sherrington assumed that synapses produce on and off responses Synapses vary enormously in their duration of effects – The effect of two synapses at the same time can be more than double the effect of either one, or less than double  Eccles Dale © Cengage Learning 2016  Types of Synapses Electrical – current flow through gap junctions Chemical – neurotransmitters  Electrical Synapses A few special-purpose synapses operate electrically Faster than all chemical transmissions Gap junction: the direct contact of the membrane of one neuron with the membrane of another Depolarization occurs in both cells, resulting in the two neurons acting as if they were one A Gap Junction for an Electrical Synapse  Electrical Synapses When speed is needed Electrical synapses can synchronize the firing of different neurons rhythmically Why not using only electrical synapses??? – Plasticity – Regulation © Cengage Learning 2016  Chemical Synapse The junction where messenger molecules (neurotransmitters) are released from one neuron to excite or inhibit the next neuron Most synapses in the mammalian nervous system are chemical  Otto Loewi’s work contributed to demonstrate the chemical nature of synapses © Cengage Learning 2016  ‘Anatomy’ of the Chemical Synapse  Tripartite synapses astrocyte excitability variations of Ca2+ concentration in the cytoplasm Gliotransmitters Glutamate ATP/Adenosine d-Serine TNFα GABA © Cengage Learning 2016  “Quad-partite" synapses Schafer et al., 2013 © Cengage Learning 2016  Neurotransmission in 5 Steps Anterograde synaptic transmission is the five-step process of transmitting information across a chemical synapse from the presynaptic side to the postsynaptic neuron: 1. The neurotransmitter is synthesized somewhere inside the neuron. 2. It is packaged and stored within vesicles at the axon terminal. 3. It is transported to the presynaptic membrane and released into the cleft in response to an action potential. 4. It binds to and activates receptors on the postsynaptic membrane. 5. It is degraded or removed, so it will not continue to interact with a receptor and work indefinitely.  Neurotransmission in 5 Steps 2 3 5 4 © Cengage Learning 2016  Steps 1 and 2: Neurotransmitter Synthesis, Package, and Storage Neurotransmitters are derived in two general ways. – Synthesized in the axon terminal (small-molecule) Building blocks from food are pumped into cell via transporters, protein molecules embedded in the cell membrane – Synthesized in the cell body According to instructions in the DNA (peptide transmitters) Transported on microtubules to axon terminal © Cengage Learning 2016  Step 3: Neurotransmitter Release At the terminal, the action potential opens voltage- sensitive calcium (Ca2+) channels. Ca2+ enters the terminal and binds to the protein calmodulin, forming a complex. The complex causes some vesicles to empty their contents into the synapse and others to get ready to empty their contents. © Cengage Learning 2016  Step 4: Receptor-Site Activation After release, the neurotransmitter diffuses across the synaptic cleft to activate receptors on the postsynaptic membrane. Transmitter-activated receptors – Protein embedded in the membrane of a cell that has a binding site for a specific neurotransmitter – Receptor properties is responsible for the effect on postsynaptic cell (same neurotransmitter can elicit different effects) © Cengage Learning 2016  Step 4: Receptor Site Activation On the postsynaptic side, neurotransmitter may 1. Depolarize the postsynaptic membrane, causing excitatory action on the postsynaptic neuron (EPSP) 2. Hyperpolarize the postsynaptic membrane, causing inhibitory action on the postsynaptic neuron (IPSP) 3. Initiate other chemical reactions that modulate the excitatory or the inhibitory effect or influence other functions of the receiving neuron Neurotransmitter may interact with receptors on the presynaptic membrane. Autoreceptor – Self-receptor on the presynaptic membrane that responds to the transmitter that the neuron releases Ionotropic receptors Metabotropic receptors © Cengage Learning 2016  Autoreceptors – Heteroreceptors – Postsynaptic receptors © Cengage Learning 2016  Autoreceptors – Heteroreceptors – Postsynaptic receptors © Cengage Learning 2016  The quantum leap How much neurotransmitter is needed to send a message? – B. Katz, recording electrical activity from postsynaptic membrane of a muscle noticed small, spontaneous depolarizations (miniature potentials); – The size appeared was a multiple of the smallest – The smallest correspond to a vesicle release, a Quantum; many quanta are required to be released at the same time to produce an AP Quantal release depends on: 1) Ca2+ entering the axon terminal in response to an AP 2) N of vescicles docked at the membrane  Step 5: Neurotransmitter Inactivation To be effective, chemical neurotransmission needs to be terminated: 1. Diffusion: some of the neurotransmitter simply diffuses away from the synaptic cleft and is no longer available to bind to receptors. 2. Degradation: enzymes in the synaptic cleft break down the neurotransmitter. 3. Reuptake: transmitter is brought back into the presynaptic axon terminal; by-products of degradation by enzymes also may be taken back into the terminal to be used again. 4. Astrocyte uptake: nearby astrocytes take up neurotransmitter; can also store transmitters for re-export to the axon terminal.  Inactivation and Reuptake of Neurotransmitters, Part 1 Neurotransmitters released into the synapse do not remain and are subject to either inactivation or reuptake During reuptake, the presynaptic neuron takes up most of the neurotransmitter molecules intact and reuses them Transporters are special membrane proteins that facilitate reuptake  Inactivation and Reuptake of Neurotransmitters, Part 2 Examples of inactivation and reuptake – Serotonin is taken back up into the presynaptic terminal (SERT) – Acetylcholine is broken down by acetylcholinesterase into acetate and choline – Excess dopamine is converted into inactive chemicals monoamine oxidase (MAO) Catechol-O-methyltransferase (COMT) enzymes that convert the excess into inactive chemicals Inactivation and Reuptake of Neurotransmitters, Part 2  Stimulant Drugs Amphetamine and cocaine – Stimulate dopamine synapses by increasing the release of dopamine from the presynaptic terminal Methylphenidate (Ritalin) – Also blocks the reuptake of dopamine but in a more gradual and more controlled rate – Often prescribed for people with ADD; unclear whether Ritalin use in childhood makes one more likely to abuse drugs as an adult Stimulant Drugs Negative Feedback from the Postsynaptic Cell Negative feedback in the brain is accomplished in two ways – Autoreceptors: receptors that detect the amount of transmitter released and inhibit further synthesis and release – Postsynaptic neurons: respond to stimulation by releasing chemicals that travel back to the presynaptic terminal where they inhibit further release  Cannabinoids The active chemicals in marijuana that bind to anandamide or 2-AG receptors on presynaptic neurons or GABA When cannabinoids attach to these receptors, the presynaptic cell stops sending In this way, the chemicals in marijuana decrease both excitatory and inhibitory messages from many neurons Effects of Some Drugs at Dopamine Synapses  A chemical with an excitatory or inhibitory effect when released by a neuron onto a target is called a(n) ____. a. molecule b. neurotransmitter c. impulse d. messenger © Cengage Learning 2016  Neurotransmitters © Cengage Learning 2016  Classes of Neurotransmitters Amino acids * Glutamate, GABA, glycine, aspartate, maybe others A modified amino acid * Acetylcholine Monoamines (also modified from amino Indoleamines: serotonin acids) * Catecholamines: dopamine, norepinephrine, epinephrine Neuropeptides (chains of amino acids) Endorphins, substance P, neuropeptide Y, Orexin, many others Purines * ATP, adenosine, maybe others Gases NO (nitric oxide), CO, H2S Fatty acids Anandamide, 2-AG * Small-Molecule Transmitters: quick-acting, synthetized from dietary nutrients and packaged in axon terminals  NEUROTRANSMITTERS T 1. Amino acids: glutamate, aspartate, serine, γ-aminobutyric acid (GABA), Y glycine P 2. Monoamines: dopamine (DA), norepinephrine (NE) (noradrenaline, NA), I epinephrine (E) (adrenaline, A), serotonin (5-HT), melatonin C 3. Acetylcholine (ACh), adenosine, anandamide, histamine A 4. Peptides (endogenous opioids, polypeptides...) L A GASSES T 1. Nitric oxide NO Y 2. Carbon oxide CO P 3. hydrogen sulphide H2S I nucleosides, such as ATP, adenosine; C and lipid-derived signaling molecules, such as A endogenous cannabinoids (anandamide (N-arachidonoylethanolamide, AEA) L and 2-arachidonoylglycerol (2-AG) endocannabinoids). 58 © Cengage Learning 2016  Synthesis of Neurotransmitters Neurons synthesize neurotransmitters and other chemicals from substances provided by the diet – Acetylcholine synthesized from choline found in milk, eggs, and nuts – Tryptophan serves as a precursor for serotonin Catecholamines contain a catechol group and an amine group (epinephrine, norepinephrine, and dopamine) Pathways in the Synthesis of Transmitters  Neuropeptides Metabotropic effects utilize a number of different neurotransmitters Neuropeptides are often called neuromodulators – Release requires repeated stimulation – Released peptides trigger other neurons to release same neuropeptide – Diffuse widely and affect many neurons via metabotropic receptors Distinctive Features of Neuropeptides Neuropeptides Other Neurotransmitters Place Synthesized Cell body Presynaptic terminal Place released Mostly from dendrites, Axon terminal also cell body and sides of axon Released by Repeated Single action potential depolarization Spread of effects Diffuse to wide area Effect mostly on receptors of the adjacent postsynaptic cell Duration of effects Many minutes Less than a second to a few seconds  Lipid Transmitters Main example: endocannabinoids (endogenous cannabinoids) – A class of lipid neurotransmitters synthesized at the postsynaptic membrane to act on receptors at the presynaptic membrane Include anandamide and 2-AG (2-arachidonoylglycerol) – Both derived from arachidonic acid, an unsaturated fatty acid Bind to CB1 and CB2 receptors THC/cannabidiol Lipid Transmitters  Gaseous and Ion Transmitters Gaseous transmitters – Neither stored in synaptic vesicles nor released from them – Synthesized in cell as needed; easily cross cell membrane Ion transmitters – Recent evidence has led researchers to classify zinc (Zn2+) as a transmitter. – Actively transported, packaged into vesicles—usually with another transmitter like glutamate—and released into the synaptic cleft –. Activating Receptors of the Postsynaptic Cell The effect of a neurotransmitter depends on its receptor on the postsynaptic cell Transmitter-gated or ligand-gated channels are controlled by a neurotransmitter  Post-Synaptic Effects Fast Synaptic Transmission (a few milliseconds) Slow Synaptic Transmission (from tenths of seconds to hours) Very Slow Synaptic Transmission (from days to years) © Cengage Learning 2016  Membrane Channels Passive channels, or leak channels active channels, or gated channels Three classes of gated channels exist: – chemically regulated channels, – voltage-regulated channels – mechanically regulated channels © Cengage Learning 2016  Neurotransmitter Receptors Membrane receptor protein activated by a neurotransmitter. Neuronal and glial cells immune and muscle tissues, etc. Autoreceptor or Heteroreceptor and postsynaptic receptor Ligand-gated receptors or ionotropic receptors G protein-coupled receptors (GPCRs) or metabotropic receptors Ligand-induced desensitization or downregulation Lack of ligand induces supersensitivity or up- regulation © Cengage Learning 2016  There are 2 main types of receptors: Ionotropic and Metabotrobic Rapid, short-acting responses vs slower longer-lasting responses involving second messangers https://www.youtube.com/watch?v=-ywRmcf1SGs © Cengage Learning 2016  cAMP as a second messenger - Modulation Modulation: no direct EPSP but make membrane more positive Increased probability of AP, Increased excitability. © Cengage Learning 2016 Depending on the G-protein, the same neurotransmitter can elicits different responses © Cengage Learning 2016  Ionotropic Effects Occurs when a neurotransmitter attaches to receptors and immediately opens ion channels Most effects: – Occur very quickly (sometimes less than a millisecond after attaching) and are very short lasting – Rely on glutamate or GABA The Acetylcholine Receptor  Metabotropic Effects and Second Messenger Systems, Part 1 Occur when neurotransmitters attach to a receptor and initiate a sequence of slower and longer lasting metabolic reactions Metabotropic synapses use many neurotransmitters such as dopamine, norepinephrine, serotonin, and sometimes glutamate and GABA  Metabotropic Effects and Second Messenger Systems, Part 2 When neurotransmitters attach to a metabotropic receptor, it bends the receptor protein that goes through the membrane of the cell – Bending allows a portion of the protein inside the neuron to react with other molecules Metabotropic events include such behaviors as taste, smell, and pain Sequence of Events at a Metabotropic Synapse  G-Proteins G-protein activation: coupled to guanosine triphosphate (GTP), an energy storing molecule – Increases the concentration of a “second- messenger” – The second messenger communicates to areas within the cell – May open or close ion channels, alter production of activating proteins, or activate chromosomes  Ionotropic vs Metabotropic - Structure © Cengage Learning 2016  Classes of Ionotropic Receptors Glutamate GABAA © Cengage Learning 2016  Classes of Metabotropic Receptors ACh © Cengage Learning 2016  Neurotrasmitters/Neuromodulators © Cengage Learning 2016  Neurotrasmitters/Neuromodulators Peptides: Substance P, Vasopressin (ADH), Orexin, opiod (enkephalins, endorphins, pain relief), often co-released with other neurocrines. Lipids: endogenous cannabinoids, CB1 receptors in brain, CB2 in the periphery (?) © Cengage Learning 2016  Metabotropic receptors ▪ Most common receptor type ▪ Coupled to G-protein (guanine nucleotide binding proteins) ▪ No direct control of ion channels ▪ ‘Multiplier effect’ of second messengers [A] [B] © Cengage Learning 2016  G protein-coupled receptors (GPCRs) © Cengage Learning 2016  G protein-coupled receptors (GPCRs) 1. regulate the changes in K+ conductance independently of second-messenger production (GABAB, α2-adrenergic, D2- dopaminergic or muscarinic M2) 2. adenylyl cyclase activity (+ β2-adrenergic receptor, or -α2- adrenergic receptor) protein kinase A (PKA) 3. PI-PLC with the attendant breakdown of PIP2 and formation of IP3 and DAG changes in Ca2+ homeostasis and protein phosphorylation via the action of protein kinase C (PKC). Other effector enzymes that may be regulated by IP3-linked GPCRs include phospholipases A2 and D. Cross-talk can occur between intracellular signaling pathways. © Cengage Learning 2016  Pathway of IP3 and DAG © Cengage Learning 2016  Different second messengers, different effects cAMP System Phosphoinositol system Arachidonic acid system First Messenger: Epinephrine (α2, β1, β2) Epinephrine (α1) Histamine (Histamine Neurotransmitters Acetylcholine (M2) Acetylcholine (M1, M3) receptor) (Receptor) ACTH, ANP, CRH, CT, FSH, Gl First Messenger: AGT, GnRH, GHRH, Oxytocin, ucagon, hCG, LH, MSH, PTH, - Hormones TRH TSH GPCR/Gs (β1, β2), Gi (α2, Signal Transducer GPCR/Gq Unknown G-protein M2) Primary effector Adenylyl cyclase Phospholipase C Phospholipase A cAMP (cyclic adenosine Second messenger IP3; DAG; Ca2+ Arachidonic acid monophosphate) 5-Lipoxygenase, 12- protein kinase A Secondary effector PKC; CaM Lipoxygenase, cycloxygenas (phosphor. K channel) e © Cengage Learning 2016  Regulation of gene expression transcription factor NF-kB (IkB+NF- kB>IkB+P / NF-kB CREB (cAMP response element-binding) Cellular Immediate-Early Genes (c-fos, fosB, c-jun, junB) (third messengers) © Cengage Learning 2016  Signal transduction to the nucleus In this schematic, activation of a neurotransmitter receptor activates cellular signals (G proteins and second-messenger systems). These signals, in turn, regulate the activation of protein kinases, which translocate to the nucleus. Within the nucleus, protein kinases can activate genes regulated by constitutively synthesized transcription factors. A subset of these genes encodes additional transcription factors (third messengers), which can then activate multiple downstream genes. © Cengage Learning 2016 © Cengage Learning 2016  Constitutive activity of GPCRs α-and β-adrenergic, histaminergic, GABAergic, Serotoninergic 2A,2C,7, opiate, and Angiotensin Ghrelin CB1 cannabinoid Rhodopsin receptors © Cengage Learning 2016  GPCRs DIMERS and crosstalk G protein-coupled receptors are composed of seven membrane-spanning alpha-helical segments, which are usually linked together into a single folded chain to form the receptor complex. Existence receptor homodimers However research has demonstrated that a number of GPCRs are also capable of forming heteromers from a combination of two or more individual GPCR subunits © Cengage Learning 2016 © Cengage Learning 2016  Receptor HETEROMERS A1/A2A heteromers and dopamine D1/D2 and D1/D3 heteromers between entirely unrelated receptors such as – CB1/A2A – mGluR5/A2A heteromers – CB1/D2 – 5-HT2AR-CB1 heteromers – 5-HT2AR-mGluR2 heteromers – CB1/A2A/D2 © Cengage Learning 2016 Drugs that Act by Binding to Receptors Many hallucinogenic drugs distort perception – Chemically resemble serotonin in their molecular shape – Stimulate serotonin type 2A receptors (5- HT2A) at inappropriate times or for longer duration than usual, thus causing their subjective effect Nicotine stimulates acetylcholine receptors  Opiate Drugs and Endorphins Opiates attach to specific receptors in the brain The brain produces certain neuropeptides now known as endorphins—a contraction of endogenous morphines Opiate drugs exert their effects by binding to the same receptors as endorphins  Hormones Chemicals secreted by a gland or other cells that is transported to other organs by the blood where it alters activity Produced by endocrine glands Important for triggering long-lasting changes in multiple parts of the body Location of Some Major Endocrine Glands  A Selective List of Hormones Organ Hormone Hormone Functions (Partial) Hypothalamus Various releasing hormone Promote/inhibit release of hormones from pituitary Anterior pituitary Thyroid-stimulating hormone Stimulates thyroid gland Luteinizing hormone Stimulates ovulation Follicle-stimulating hormone Promotes ovum maturation (female), sperm production (male) ACTH Increases Steroid hormone production by adrenal gland Prolactin Increases milk production Growth hormone Increases body growth Posterior pituitary Oxytocin Uterine contractions, milk release, sexual pleasure Vasopressin Raises blood pressure, decreases urine volume Pineal Melatonin Sleepiness; also role in puberty Adrenal cortex Aldosterone Reduces release of salt in the urine Cortisol Elevated blood sugar and metabolism Adrenal medulla Epinephrine, norepinephrine Similar to actions of sympathetic nervous system Pancreas Insulin Helps glucose enter cells Glucagon Helps convert stored fats into blood glucose Ovary Estrogens and progesterone Female sexual characteristics and pregnancy Testis Testosterone Male sexual characteristics and pubic hair Kidney Renin Regulates blood pressure, contributes to hypovolemic thirst Fat cells Leptin Decreases appetite  Proteins and Peptides Composed of chains of amino acids Attaches to membrane receptors where they activate second messenger systems The Pituitary Gland and the Hypothalamus Attached to the hypothalamus and consists of two distinct glands – Anterior pituitary: composed of glandular tissue Hypothalamus secretes releasing and inhibiting hormones that control anterior pituitary – Posterior pituitary: composed of neural tissue Hypothalamus produces oxytocin and vasopressin, which the posterior pituitary releases in response to neural signals Location of the Hypothalamus and Pituitary Gland in the Human Brain Pituitary Hormones Negative Feedback in the Control of Thyroid Hormones  Thanks You © Cengage Learning 2016  Maintaining Hormonal Levels The hypothalamus maintains a fairly constant circulating level of hormones through a negative-feedback system – Example: TSH-releasing hormone and thyroid hormone levels Some Major Events in Transmission At a Synapse  Storage of Transmitters Vesicles: tiny spherical packets located in the presynaptic terminal where neurotransmitters are held for release MAO (monoamine oxidase): breaks down excess levels of some neurotransmitters Exocytosis: bursts of release of neurotransmitter from the presynaptic terminal into the synaptic cleft – Triggered by an action potential  Release and Diffusion of Transmitters Transmission across the synaptic cleft by a neurotransmitter takes fewer than 0.01 milliseconds Most individual neurons release at least two or more different kinds of neurotransmitters Neurons may also respond to more types of neurotransmitters than they release  A neurotransmitter can affect a postsynaptic cell via two types of receptor proteins: ▪ Ionotropic (ligand-gated ion channels) - combine receptor binding and channel functions into one single entity, ie: receptor molecule is also a channel ▪ Metabotropic - the eventual movement of ions through a channel depends on one or more metabolic steps, ie: receptor and channel are separate 1 5 Ions cross membrane Neurotransmitter binds 1 Neurotransmitter binds 2 Channel opens 4 Ion channel 3 Ions flow 2 3 G-protein subunits or opens across G-protein intracellular messengers membrane activated modulate ion channels © Cengage Learning 2016  Architecture of metabotropic receptors © Cengage Learning 2016  Modulation Eg: modulation by the NE β receptor Many synapses with G-protein coupled NT receptors are not associated with an ion channel. Synaptic activation of these receptors does not directly evoke EPSPs and IPSPs, but instead modifies the effectiveness of EPSPs generated by other synapses with transmitter-gated props. © Cengage Learning 2016