BISC 421 1st Edition Lecture 11 Outline of Current LectureI. Neurotransmitters and their Receptors Continued II. Intracellular Signal Transduction Current LectureNeurotransmiters and their Receptors (continued)• Synthesis and recycling process of glutamate •Almost identical process for all of these•Presynaptic terminal with vesicles full of glutamate and receptors on post synaptic cells•Release of glutamate into the synaptic cleft, removed by transport back into pre synaptic cell or glial cells which have EATT’s that look for glutamate to transform to glutamine and bring back into cell (glutamine is precursor for glutamate)-‐ transported back into the vesicle by VGLUT•Glial cells critical for this process – controlling how much glutamine is available-‐ if get rid of glial cells, affect this system•If we screw up this system: excitotoxicity-‐ too much release of glutamate-‐ degeneration of nerves with age•If too much activation of glutamate receptors will lead to cell death•This happens over the years-‐ only happens in post synaptic cell•Only the dendrites are damaged so know this is only effecting the post synaptic cell•Get a ton of Ca2+ inside the cell-‐ which is BAD for a cell – oxidative damageThese are synthesized and released similarly•There are specific precursors for each small neurotransmitter•Cascades of synthesis require these enzymes (rate determining steps)•Main difference is have to be processed and generated from larger peptides•Processing is due to proteases-‐ chopping up larger peptides into smaller active peptides•Endorphins (start from a larger pre-‐peptide)•Can be really small or really large•Don’t need to remember all of these just know they are broken down from larger peptides•Pay attention to: acetylcholamine, GABA•Hyperpolarize the cell•Cl-‐ selective ION channel instead of K+ selective channel like in glutamate•Pentamer•Several types of GABA receptors•When channel is open allows Cl-‐ to flow inward (considered outward current)•How do we make GABA? Similar mech•Requires a vesicular transporter to get into the vesicle•Gets releasedglial cells responsible for recycling•TRANSPORTERS CRITICAL FOR PROCESS•Last set of NT’s that we will talk about•Plants make these chemicals that will affect endogenous pathways•Works because there are endogenous molecules called endocannabinoids•Molecules that body makes that mimic THC are anadamide and 2AGIn the developing brain, GABA can lead to post-synaptic excitation. Due to a different ECl at these early stages.-50 mV in the developing brain -70 mV in the adult brain.A Na+/K+/Cl- co-transporter is highly expressed in the immature neuron. Leads to a higher intracellular concentration of With maturation, a K+/Cl- co-transporter begins to be expressed.Ń Pumps out Cl-, thus lowering the intracellular concentration.Activity induces the production of endocannabinoids which work to control GABA release. Increased Ca2+ in the post-synaptic cell leads to endoC production and subsequent release from the cells. Diffuse back to the pre-synaptic cell and through CB1 GPCRs, lead to reduced release of GABA from the nerve terminal. Likely through affects on voltage-gated Ca2+ channels or K+ channels, although not entirely clear. Can be blocked by antagonizing CB1 receptors.•Role is actually modulatory in neurotransmission•They affect inhibitory mechanism•A lot of activity will produce the triggering of endocannabinoids•If there is too much stimulation (GABA) in post synaptic cell it will generate the endocannabinoids to be released in the postsynaptic cell where they will diffuse out to the presynaptic cell to affect release of GABA from the presynaptic cell•Like a negative feedback system-‐ or “retrograde control” when cell is over stimulatedGABA is actually excitatory during development-‐ this is because your extracellular Cl- ‐concentration during development is actually less than intracellular concentration- ‐meaning that Cl-‐ (because the equilibrium potential of Cl-‐ actually is -‐50 mV or more positive than when you are older-‐ also this Na+/K+/Cl-‐ transporter in developing cell keeps intracellular concentration of Cl-‐ high) will flow out of the cell, depolarizing the cell•But when you get older, the Ecl becomes more negative meaning that the Cl-‐ will move into the cell, hyperpolarizing the cell. In the mature cell, new K+/Cl-‐ co transporter keeps intracellular concentration of Cl-‐ lower•It is important for GABA to be excitatory during developmentNeurons can synapse with thousands of other neurons. Both excitatory and inhibitory.Two interneurons labeled with MAP2 (green). Only in dendrites. Synaptogamin is in red. Labels only presynaptic terminals.•What happens to neurons that are synapsed with multiple cells? How do we get AP?•Green labeling-‐ only in dendrites•Red-‐ synaptotagmin in the presynaptic cell-‐ every single dot is another neuron synapsing with these cells• Neuron not just receiving one response•Whether we get excitation or inhibition is dependent upon summation of signals•One neuron that has 2 excitatory connections and 1 inhibitory•One signal not enough to cause depolarization but if activated at the same time it is enough to reach threshold and cause AP•If we just activate the one inhibitory neuron when activating both excitatory, notenough to get over threshold due to summation•Whether a cell will fire an action potential is due to a summation of the EPPs•1. Reception-‐ signaling molecule binds receptor•2. Transduction-‐ relay of signals in the cell (by changing enzyme activity or gene transcription)•3. Response•Paracrine•Endocrine•At the end the signals need to bind to some sort of cell receptor if cell-‐impermeant•There are cell permeant-‐ Nitric Oxide•Cell associated-‐ just come in contact to changeCell receptors:•1. Ion channels•2. G protein coupled•3. Enzyme linked-‐ membrane proteins looking for a signal but they will act like enzymes•4. Intracellular receptors•G protein coupled receptors•3 different types of neurotransmitter G protein receptors•Norepinephrine-‐ B adrenergic•1. B adrenergic-‐ affects cAMP in excitatory way•2. Dopamine D2-‐ affects cAMP in inhibitory way•Glutamate-‐ mGluR-‐ affects phospholipidsEnzyme linked receptors•Classical example is NGF•RTK