5 – Neurochemistry 1 (A Survey of Neurotransmitters and Their Receptors) – Flashcards
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What are the defining characteristics of Neurotransmitters?
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1. Vesicular Storage at the Presynaptic Terminal; Stored in presynaptic vesicles 2. Release in a Ca²⁺ dependent Manner 3. Capable of interaction with a Membrane-bound Receptor to produce an effect (action identical to endogenous transmitter)
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What is a Neuromodulator?
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A term used to reference a substance that may have similar effects to a neurotransmitter; not enough evidence to satisfy all three conditions or A term used to reference a substance that has a long-lasting effect (however, neurotransmitters can also have long lasting effects, though they are typically short lived) Extra Note: To determine meaning of term, consider context in which it is used
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How do small molecule neurotransmitters look in electron micrographs?
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They appear in clear vesicles
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How do peptide neurotransmitters look in electron micrographs?
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They appear in large, dense-core vesicles
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Is speed of transmission (fast or slow) a function of receptor type or neurotransmitter type?
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Speed of transmission is normally a function of the receptor type (*NOT* the neurotransmitter type)
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What are the speeds of ionotropic transmission and of metabotropic transmission?
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- As a general rule, ionotropic transmission is fast (fEPSPs or fIPSPs) and metabotropic transmission is slow (sEPSPs or sIPSPs) - Exceptions do exist, e.g. GABA-C R is slow but ionotropic - Any given neuron may have a collection of types
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Describe GABA-C Receptor transmission.
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Slow, but ionotropic (exception to the rule that ionotropic is normally fast and metabotropic is normally slow)
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What is Temporal Summation?
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Integration of EPSPs generated in rapid succession at the same synapse; stimulating another time before the last EPSP has died off, the second EPSP willed onto or sum with the first EPSP; multiple EPSPs in succession add up to breach the threshold, one ESPS will not be enough to breach threshold alone; postsynaptic potentials produced in rapid succession in the same synapse combine to form a greater signal; A presynaptic neuron fires action potentials so rapidly that the EPSPs or IPSPs pile on top of each other
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What are fast Excitatory Postsynaptic Potentials (fEPSP) typified by?
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nAChRs, AMPA or Kainate GluRs
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What is an example of a receptor that produces fast Inhibitory Postsynaptic Potentials (fIPSP)?
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GABA-A Receptor
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What is an example of a receptor that produces slow Inhibitory Postsynaptic Potentials (sIPSP)?
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GABA-B Receptor
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Peptide transmitters are normally fast or slow? Excitatory or inhibitory?
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- Normally slow (have to be broken down by peptidases which takes time) - Can be excitatory or inhibitory
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Describe chick ciliary ganglion cells transmission.
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Acetylcholine activates sEPSP and fEPSP, and VIP, SP and enkephalin produce very slow effects
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True or False: Dendrites can act as presynaptic compartments in some cases.
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True
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What are Presynaptic Autoreceptors?
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Receptors for a neurotransmitter that are located on the same cell that releases the neurotransmitters (application: negative feedback through hyperpolarization of presynaptic cell)
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What are Presynaptic Heteroreceptors?
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Receptors for an neurotransmitter that are on a different cell than the one that releases the neurotransmitter (application: negative feedback to presynaptoc cell via axoaxonic synapse with a third neuron)
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What are two examples of presynaptic inhibition using Presynaptic Heteroreceptors?
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Serotonin and Enkephalin
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Describe Ionotropic Neurotransmission.
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- Also known as Ligand-Gated Ion Channel - Defining Characteristic: Receptor molecule itself contains the ion channel/pore - Binding of neurotransmitter causes conformational change that opens channel
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Ionotropic neurotransmission is mediated by which neurotransmitters/what are examples of neurotransmitters that use ionotropic receptors?
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1. Acetylcholine (Nicotinic) 2. Glutamate (AMPA) 3. Glycine (for conducting Cl- ions, produces inhibitory effect, makes interior more inhibitory) 4. GABA-A (for conducting Cl- ions, produces inhibitory effect, makes interior more inhibitory) Extra Note: Glutamate receptor (AMPA) has 4 subunits, remainder of neurotransmitters listed have receptors that have 5 subunits, also except for glycine, the above neurotransmitters can also bind metabotropic receptors
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G-Protein Coupled Receptor neurotransmission is mediated by which molecules?
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Neurotransmitters: Catecholamines, Serotonin Peptide hormones: Glucagon Rhodopsin (opsin)
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Describe the structure of a G-Protein Coupled Receptor.
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- 7 transmembrane domains - Single subunit (or in some cases, dimer) receptor (note that ionotropic have ~4-5 subunits in comparison) - coupled with heterotrimeric G-protein via intracellular loop
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How do G-Protein Coupled Receptors work?
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Can be coupled to either an ion channel or second messenger system
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What are the characteristics of G-Protein Coupled Receptor transmission?
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- Late onset - Long duration
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Examples of G-Protein Coupled Receptors?
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1. Muscarinic Acetylcholine Receptors (mAChRs) 2. D2 Dopamine Receptor
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sEPSPs usually involved G-protein coupling, i.e.
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Muscarinic AChRs, metabotropic GluRs
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Compare and contrast Nicotinic Acetylcholine Receptors (nAChR) and Muscarinic Acetylcholine Receptors (mAChR)
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- Both respond to Acetylcholine - *Nicotinic is an ionotropic* receptor that does *fast* transmission as a ligand-gated ion channel - *Muscarinic is a G-Protein Coupled Receptor (metabotropic)* that does *slow* transmission via second messengers - Nicotinic is more sensitive to Nicotine than Muscarine and vise versa for Muscarinic
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What is the purpose of having different G-protein subtypes? What are the four G-protein subtypes found in the brain?
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Purpose: Different types of G-proteins will regulate different downstream processes Subtypes: 1. Gs 2. Gi 3. Gq(p) 4. Go
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The *Gs* subtype of alpha subunit has what effect(or)?
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Causes an *increase* in Adenylyl Cyclase (an enzyme that converts AMP to cAMP) which is correlated to excitation (*s*timulation)
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The *Gi* subtype of alpha subunit has what effect(or)?
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Causes a *decrease* in Adenylyl Cyclase (an enzyme that converts AMP to cAMP) which is correlated to *i*nhibition
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The Gq(p) subtype of alpha subunit has what effect(or)?
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Causes an increase in Phospholipase C
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The Go subtype of alpha subunit has what effect(or)?
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1. Causes K channels to *open* (and thus cause EPSP/IPSP) 2. Causes Ca channels to *close/become less active*
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Given the second messenger Cyclic AMP (cAMP) list: A. The Precursor molecule B. The Enzyme of Synthesis C. G-Protein D. Its target(s)
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A. ATP B. Adenylyl Cyclase (aka Adenylate Cyclase) C. Gs or Gi D. Cyclic Nucleotide-Gated Ion channels, Cyclic AMP-dependent kinase (PKA)
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Given the second messenger Diacylglycerol (DAG) list: A. The Precursor molecule B. The Enzyme of Synthesis C. G-Protein D. Its target(s)
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A. PIP₂ B. Phospholipase C C. Gq(p) D. Protein Kinase C (PKC)
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Given the second messenger Inositol Triphosphate (IP₃) list: A. The Precursor molecule B. The Enzyme of Synthesis C. G-Protein D. Its target(s)
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A. PIP₂ B. Phospholipase C C. Gq(p) D. Receptor on Endoplasmic Reticulum
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Given the second messenger Ca²⁺ list: A. Source B. ? C. ? D. Its target(s)
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A. Endoplasmic Reticulum (ER) B. NMDA receptor C. Voltage-Gated Channels D. Protein Kinase C (PKC), Calmodulin, Ca²⁺/Calmodulin dependent Protein Kinase (CaMK)
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Which receptor uses Gs to initiate the cAMP second messenger?
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D1 dopamine receptor (thus it causes an increase in Adenylyl Cyclase)
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Which receptor uses Gi to initiate the cAMP second messenger?
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M2 AChR and D2 dopamine receptors (thus they cause a decrease in Adenylyl Cyclase)
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Cyclic nucleotide-gated channels (CNG) conduct which ions?
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Na, K and Ca fairly non-selectively
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True or False: CNG channels are voltage-gated.
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Although they show very little voltage dependence, they technically belong to a superfamily of voltage gated channels
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Where are CNG channels largely found?
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Retinal photoreceptors and olfactory sensory neurons
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What is Achromatopsia?
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Color Blindness Caused by mutations in the A and B subunits of CNG channels expressed in human cone cells
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How many cAMP does it take to activate PKA catalytic subunits?
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4 There are two regulatory subunits, two cAMP bind to each
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Describe Calmodulin (CaM).
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- 17 kDa protein - Four calcium binding sites per molecule of calmodulin - The complex of calcium/calmodulin regulates multiple enzymes
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Calmodulin with 4 bound Ca ions bound (Calcium/Calmodulin complex) regulates which four enzymes?
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1. Calcium/Calmodulin dependent Protein Kinase (CaMK) 2. Ca2+-ATPase pump 3. some subtypes of adenylate cyclase 4. Phosphodiesterase
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How is Synaptotagmin related to Calcium?
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Synaptotagmin is the Calcium sensor for neurotransmitter release
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Where do protein kinases phosphorylate neuronal proteins (which residues)?
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Serine and Threonine
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What determines the specificity of a response/effect of a neurotransmitter?
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The receptor type (one neurotransmitter can have more than one receptor)
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List the possible receptors for Catecholamines.
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Dopamine (a Catecholamine): D1 - D5 Receptors Norepinephrine (a Catecholamine): Alpha1, Alpha2, and Beta
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What is the effect of the D1 or D5 receptors?
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Increase in Adenylyl Cyclase
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What is the effect of the D2-D4 receptors?
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Decrease in Adenylyl Cyclase
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What is the effect of Alpha1 receptors for norepinephrine?
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Increase in Phospholipase C
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What is the effect of Alpha2 receptors for norepinephrine?
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Decrease in Adenylyl Cyclase
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What is the effect of Beta receptors for norepinephrine?
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Increase in Adenylyl Cyclase
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What is the effect of the Nicotinic Acetylcholine Receptor (nAChR)?
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Na/K conductance
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What is the effect of the Muscarinic (M1, M3, M5) Acetylcholine Receptors (AChR)?
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Increase in Phospholipase C
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What is the effect of Muscarinic (M2, M4) AChR effect
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Decrease Adenylyl Cyclase and G-protein coupling to ion channels
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What is the effect of GABA-A receptors?
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Cl- conductance, fast acting
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What is the effect of GABA-C receptors?
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Cl- conductance, slow acting
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What is the effect of GABA-B receptors?
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K/Ca conductance (They are G-Protein Coupled)
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What is the effect of AMPA/Kainic acid receptors?
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Na/K conductance
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What is the effect of the NMDA receptor?
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Na/K/Ca conductance (has both ligand-gated and voltage-gated properties)
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What is the effect of the Metabotropic Glutamate Receptor (GluR)?
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Increase in Phospholipase C
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What are some intracellular targets for protein kinase enzymes?
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- Ion channel proteins - Other enzymes (tyrosine hydroxylase; has 4 sites for PO4) - Cytoskeletal proteins (microtubule-associated proteins, Tau) - Transcription factors (cAMP Response Element Binding Protein, aka. CREB) - Some substrates are the target of multiple kinases (Tyrosine hydroxylase)
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Describe the receptor subtypes for Norepinephrine.
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Alpha1 - Gq coupled, increase PLC Alpha2 - Gi coupled, decrease cAMP All Beta (1,2,3) - Gs coupled, increase cAMP Gq increases Ca2+ release from ER and activates PKC via DAG. Ca2+/Calmodulin interacts with: 1) CaMK (Calcium/Calmodulin-dependent protein kinase) 2) Ca2+ ATPase pump 3) Some subtypes of adenylyl cyclase and phosphodiesterase
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Describe the receptor subtypes for GABA.
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3 receptors GABA (A-C) GABA-A: Increases Cl- conductance (fast, ionotropic) GABA-B: Gi-coupled; increases K+ conductance, decreases Ca2+ conductance GABA-C: Increases Cl- conductance (slow, ionotropic)
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Describe the receptor subtypes for Glutamate.
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AMPA/Kainic Acid receptor: ionotropic (Na+/K+ conductance). AMPA is faster than Kainic acid receptor! NMDA receptor: ionotropic (Na+/Ca2+ channel, K+ leaks out when open; Mg2+ and Zn2+ block channel until cell depolarizes enough for them to dissociate from the receptor) Metabotropic (mGluR): mGluR1 and mGluR5 - Gq-coupled mGluR2-8 (except 5) - Gi/Go-coupled Go increases K+ conductance, decreases Ca2+ conductance**
