PSL300 Week 1-12 Lecture Notes PDF

Lecture 1: Transport Mechanisms Cell Membrane Cell membrane = made of phospholipid bilayer B/c of this lipid-soluble/NP molecules (gases) diffuse easily & water-soluble/P molecules need help of channels to cross o Impermeable to organic anions (pro...

Lecture 1: Transport Mechanisms Cell Membrane Cell membrane = made of phospholipid bilayer B/c of this lipid-soluble/NP molecules (gases) diffuse easily & water-soluble/P molecules need help of channels to cross o Impermeable to organic anions (proteins) -> remain on the inside of a cell NOTE: Permeability depends on molecular size, lipid solubility & charge Membrane Permeability Membrane is permeable to molecule X, if molecule X can cross in any way o Gases diffuse out easily, but polar molecules & ions need help of protein channels or carriers to cross Simple Diffusion: Small, lipid-soluble molecules & gases (CO2, O2) pass either directly through phospholipid bilayer or through pores Membrane Channels o Subs. moves down its [ ] gradient (high [ ] -> low [ ]) o Rate of diffusion is roughly proportional to [ ] gradient Membrane-spanning proteins -> forms pore in membrane across membrane (greater [ ] gradient -> greater rate o Made of 4-5 protein subunits fit together -> central pore of diffusion) created through membrane o Passive; no energy input from ATP o Allows specific ions to diffuse through Facilitated Diffusion: molecules diffuse across membrane w/ Has pore loops that dangle inside channel -> create selective help of carrier protein (req. b/c molecule cannot move filter for size & charge through membrane via simple diffusion) These channels are not generally kept open; they can be closed o Carrier proteins (NOT PORES) aids w/ movement of by a part of the channel called a gate polar molecules (sugars & AAs) o Sometimes gate is closed -> no diffusion & sometimes o Movement down [ ] gradient gate is open -> diffusion occurs (selective tho) o Passive; no energy input from ATP Proteins can shift b/t 2 shapes: open pore/ closed pore o NOTE: transporter proteins are limited, meaning that if Ligand Gated Channels: binding of ligand to a receptor on the you have a lot molecules to be transported, only the max. membrane -> triggers events @ membrane (activation of # of molecules can be moved (all proteins are occupied/ enzyme/ cellular responses saturated) o Ex. Synaptic transmission (neurotransmitters -> post- Active Transport: mechanism to move selected molecules synaptic cleft) across cell membranes, against their [ ] gradient Voltage Gated Channels: Changes in MP -> induces o Subs. binds to protein carrier -> changes conformation - conformation change in channel’s subunits -> diffusion pore > move subs. across created o Active; req. energy input from ATP hydrolysis o Has S4 segment (in 4th transmembrane domain)-> o Ex. Na+/K+ Pump/ ATPase senses changes in MP Secondary Transport: subs. is carried against its [ ] o When resting/polarized (-70mV): S4 segments are gradient w/o ATP hydrolysis +ively charged -> attracted to -ive charge of intracellular o Movement of 1 subs. down its [ ] gradient -> powers membrane layer -> S4 segments move downward -> movement of another subs. against its [ ] gradient keeps channel shut (chemical energy); therefore no need for ATP o When depolarized (-55mV): S4 segments still remain o Binding of 1 subs. & ions to specific sites on transporter +ively charged -> attracted to -ive charge of extracellular -> conformation change of protein membrane layer -> S4 segments move upward-> opens channel This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:06:33 GMT -05:00 https://www.coursehero.com/file/119193971/Lec1-Transport-Mechanismspdf/  Endo/Exocytosis Endocytosis: inward ‘pinching’ of membrane to create a vesicle; usually receptor-mediated to capture proteins, from outside -> inside Exocytosis: partial/complete fusion of vesicles w/ cell membrane for bulk trans-membrane transport of specific molecules, from inside -> outside. o Exocytosis 1 aka Kiss and Run: secretory vesicles dock & fuse w/ plasma membrane @ specific locations call fusion pores; vesicle connect & disconnect many times before all/most contents are emptied (each kiss empties part of the contents; used for low rate signaling o Exocytosis 2 aka Full Exocytosis: complete fusion of vesicle w/ membrane -> total release of vesicle contents @ once; necessary for delivery of membrane proteins; used for high rate signaling o NOTE: Exocytosis 2 MUST be counterbalanced w/ endocytosis to stabilize membrane SA -> or there would be too much membrane -> loose membrane -> bad!! Membrane Potential MP: diff. in potential across a cell’s membrane We nee MP to create a short electrical impulse (AP) Resting Membrane Potential NOTE: All cells have a non-zero MP & to create a MP 1. Create [ ] gradient: enzyme ion pump (ATPase) must We know that our RMP is NOT -10mV, it’s -70mV actively transport ions across membrane to make [ ] o Something else is happening -> K+ ions diffusing outwards gradient o This is created by resting membrane being most permeable 2. Semi-permeable membrane: allows 1 ion species to to K+ ion than other ions (condition #2 for MP) via K+ leak diffuse thru membrane more easily than others (more channels permeable to 1 ion) -> diffusion of this ion down its [ ] o +ive charge accumulates on outside & -ive inside -> MP gradient creates electrical gradient more -ive than -10mV Na+/K+ Pump: ATPase that moves 3 Na+ out & 2 K+ in per 1 Efflux occurs until there’s buildup of +ive charge on outside of ATP-> creates [ ] gradient for Na+ & K+ membrane o All cell membrane has this -> req. for all living cells o This +ive charge repels further diffusion of K+ ion towards o Consumes lots of energy outside o Na+/K+ inequality -> Potential diff of -10mV b/c net 1 o This is equilibrium potential (specifically for K+ ion): +ive charge moving out electrical work to repel outward cation diffusion = chemical work of diffusion down [ ] gradient o Use Nernst Equation to calculate equilibrium potential of a specific ion (& only 1!) which depends on [ ] gradient: Eion = (RT/F) ln([ion]out /[K+]in) o We calculate the equilibrium potential for K+ we get -90mV not22:06:33 This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 -70mV,GMT Why?-05:00 (NOTE: -90mV is the MP if only K+ ions were involved https://www.coursehero.com/file/119193971/Lec1-Transport-Mechanismspdf/ Powered by TCPDF (www.tcpdf.org)  Lecture 2: Resting Membrane Potential Membrane Potential Why is RMP -70mV & not -90mV? o Membrane is most permeable to K+ @ rest than any other ion (40x more), but Na+ & Cl- still contribute to the RMP o K+ leaves cell -> MP more -ive (-90mV) & there is influx of Na+ ions (counteracting the movement of K+ leaving or -ive intracellular potential) -> MP less -ive/more +ive than -90mV, but still will be close to -90mV b/c membrane most permeable to K+ So in order to calculate the RMP, we must create another equation to consider all of the ions & each of their permeabilities (K+, Na+, Cl-); K+ will always have the highest permeability o Goldman Equation is the expanded version of the Nernst eq.; NOTE: P is the permeability vals given to each ion species & an ion w/ a P=0, will drop out of the equation (Ex. Ca2+) o Using this equation we see that the Em = -70mV Na+ Equilibrium Potential: if the membrane were to be most permeable to Na+ then there would be a net influx of Na+ (remember Na+ is most [ ]ed on the outside) -> net cation accumulation on inside o ENa+= = 60mV (if membrane was only permeable to Na+) Cl- ions: o Intracellular there are large proteins that tend to be -ive -> due to electrostatics (like repels like) -> Cl- ion is pushed out of cell -> therefore Cl- ion is more [ ]ed extracellularly Na+ Voltage-Gated Channels: to create AP, membrane must increase its conductance by opening channels permeable to only Na+ ion o @ RMP, Na+ Voltage-Gated Channels are closed -> to open -> membrane needs to be depolarize (make intracellular environment more +ive) o Open @ -55mV (NOTE: This is NOT RMP) o How does Na+ Channels open: 1. MP reaches -55mV (threshold potential) 2. S4 segments move upward b/c of attraction to -ive charged extracellular membrane -> activation gate opens 3. Pore is opened b/c S4 segment is not obstructing passage -> allows Na+ to move from out -> in o After Na+ is allowed to move in -> rapid depolarization occurs: When 1 area on membrane depolarizes -> causes other channels to open -> causes other areas of membrane to depolarize -> repeats & Na+ is also attracted to -ive intracellular environment o How does Na+ Channels close: 1. After 0.5 ms of opening of Na+ channel -> inactivation gate swings shut (Ball & Chain) 2. Prevents further Na+ movement (halts rapid depolarization) o NOTE: if there was no inactivation gate -> MP would reach +60mV (ENa+) o To remove inactivation gate -> MP needs to fall below -55mV; aka as reactivating Na+ channel and going back to original conformation -> allows for another AP This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:07:02 GMT -05:00 https://www.coursehero.com/file/119194103/Lec2-Resting-Membrane-Potentialpdf/  Action Potential Threshold: Min. depolarization necessary to induce the regenerative mechanism for the opening of Na+ channels AP: very short-lived (impulse) change in MP; used as a signal o Subthreshold stimuli (less than 15mV stimulus): some o Can make APs in membrane that contains enough of the Na+ Voltage-gated channels open, but not enough to reach voltage-gated Na+ channels b/c they makes the threshold potential (-55mV) -> no AP membrane ‘excitable’ o Threshold stimuli (15mV stimulus): enough Na+ Voltage- o When Na+ channels are open -> rapid depolarization gated channels open -> reached threshold potential (- towards ENa+= +60mV -> but will inactivate w/in 0.5 ms 55mV) -> AP o After inactivation of Na+ channels -> K+ Voltage-gated o Suprathreshold stimulus (more than 15mV stimulus): channels dominant -> repolarizing membrane to RMP via more than enough Na+ Voltage gated channels open -> K+ moving inside -> outside reached threshold potential (-55mV) -> AP o NOTE: K+ leak channels are always open -> so you always o NOTE: both Threshold & Suprathreshold stimulus will cause have K+ leaving the cell an AP of same magnitude regardless of amount of Steps of AP: stimulus provided 1. @ RMP = -70mV; NOTE: activation gate is closed & inactivation o Frequency of APs coding for the intensity of the stimulus; gate is open. more APs in time unit -> strong stimulus & less or 1 AP in 2. Stimulus -> slow increase of MP time unit -> weak stimulus 3. MP reaches -55mV (threshold potential) -> Voltage-gated Na+ Refractory Period: After generating AP -> Na+ Voltage-gated (activation gate opens & inactivation gate is still open) & K+ channels inactivate -> prevents firing of another AP until MP channels begin to open (Na+ channels are faster at opening and drops below -55mV to allow for reconfiguration of Na+ Voltage- K+ channels are slower) gated channels to make membrane excitable 4. Rapid Na+ influx -> rapid depolarization (increased PNa+) o Absolute RP: All of Na+ Voltage-gated channels are 5. Na+ Voltage-gated channels close b/c of inactivation gate inactivated (none are reconfigured) -> NO GENERATION swinging shut (decreased PNa+) & slower K+ Voltage-gated OF AP AT ALL channels open; NOTE: Activation gate of Na+ Voltage-gated o Relative RP: Some but not all Na+ Voltage-gated channels channels is still open b/c membrane is still depolarized but are inactivated (some are reconfigured) b/c they don’t inactivation gate is shut -> Na+ doesn’t move intracellularly act in unison & reconfigure @ diff. speeds -> CAN 6. K+ moves extracellularly (increased PK+) -> repolarization GENERATE AP but smaller b/c of fewer Voltage-gated 7. K+ Voltage-gated channels remain open -> more K+ leaves -> Na+ channels available after-hyperpolarization (less than -70mV, undershoots); after Can block membrane from producing AP -> keep membrane MP reaches below -55mV -> some NOT ALL Na+ Voltage-gated depolarized -> Na+ Voltage-gated channels will be permanently channels begin to reconfigure (inactivation gate is removed + inactivated (permanent absolute RP) -> cannot generate activation gate closes again) another AP (membrane is in-excitable) 8. Voltage-gated K+ channels close, less K+ leaves cell (there are o How? Destroy K+ [ ] gradient (b/c K+ keeps MP @ -70mV) still K+ leak channels) -> (decreased PK+) via introducing more K+ in extracellular space (Ex. KCl 9. Eventually return to RMP b/c of resting ion permeability -> injection) ready for another AP This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:07:02 GMT -05:00 https://www.coursehero.com/file/119194103/Lec2-Resting-Membrane-Potentialpdf/ Powered by TCPDF (www.tcpdf.org) Lecture 3: Action Potential Conduction Impulse Conduction When patch of excitable membrane generates AP -> causes influx of Na+ & reverses potential diff. across membrane (depolarization) o Temporary reversal of potential goes from -70mV -> +30mV o This is source of depolarizing ‘force’ for the adjacent membrane -> Na+ channels in adjacent membrane open as result (occurs via electromagnetism -> conduct electricity) o This is how AP propagates (move) from origin -> to rest of cell (like a ‘wave’) Excitable Cells o These cells have Voltage-gated Na+ channels -> allows for generation of APs + long axons -> carry a signal for long dist.; both conditions allow for propagating APs o Axons: long extension of cell body to carry AP to other loc. (wire) o Cells that lack Voltage-gated Na+ channels can still conduct passive currents, but cannot generate APs o Cells that don’t want to carry signal for a dist. -> no axon Experiment: Myelination: process of special glial cells (Schwann cells -> o In biological tissue, putting voltage across membrane will PNS & Oligodendrocytes -> CNS) wrap successive sections of result in a loss of voltage (loss of sharp freq.) -> this is b/c axon w/ myelin sheath (layers) biological tissue is not a great conductor compared to o This ↑ membrane resistance & is the most efficient way of copper wire ↑ conduction velocity o This is must mean membrane composition & property shapes o NOTE: Glial cells req. for myelination & nutrition form of signal -> how do we prevent loss of signal? o There are ~ 50-100 layers of myelin sheath around axon -> ↑ membrane resistance greatly -> ↓leakage of current out Cable Properties of membrane -> ↑  by 20x, but takes space o NOTE: Only 20% of cells are myelinated, these are cells Length constant (): measures how far AP can travel before that mainly have to deliver signals really far) dying off (goes to 37% of original val) Schwann cells wrap around 1 portion of 1 axon & cytoplasm is o Therefore, conduction velocity of AP along axon depends on  squeezed out o Therefore, ↑ -> longer dist. AP travels (very ideal) Oligodendrocytes have many processes (‘arms’) that reach like o To ↑ -> ↑ diameter b/c larger diameter -> ↓internal an octopus & wrap many axons individually resistance -> less voltage loss due to resistance (caused Nodes of Ranvier: Small gaps b/t portions of myelin sheaths from organelles) where AP is regenerated/ replenished by allowing Na+ to move o To ↑ -> ↑ membrane resistance b/c larger membrane w/o myelin in the way through Voltage-gated Na+ channels resistance -> ↓current leaking -> more current is forced Multiple Sclerosis (MS): condition where myelin sheath is down membrane (think of wrapping straw w/ tape to prevent destroyed -> slowed/blocked signals -> causes symptoms of leakage) visual disturbances, muscles weakness etc. o  can be calculated from internal resistance (Ri) & membrane resistance (Rm); NOTE: extracellular fluid resistance (Ro) is not used because its composition doesn’t change: o From the equation we see that to ↑ -> ↑ diameter/↓ Ri & To -> downloaded ↑was This study source ↑ membrane resistance (closefrom by 100000818475141 holes to prevent on 10-03-2024 22:07:20 GMT -05:00 CourseHero.com leakage) https://www.coursehero.com/file/119194231/Lec3-Action-Potential-Conductionpdf/  Saltatory Conduction: when AP ‘jump’ from one node to the next node & in b/t (myelin sheath) you are not generating AP, but conducting AP passively o NOTE: @ nodes you are generating APs (these areas are excitable) o NOTE: when node has AP, this depolarizing current is strong enough to travel down axon for many nodes (~ 5-10) -> provides enough depolarizing current for those nodes to threshold potential (-55mV) -> allowing for next 5-10 nodes to Axon Terminal simultaneously generate APs & passive spread and prevention of leakage of current b/t nodes (myelinated areas) We know that AP will conduct down membrane -> axon terminal o The furthest node will determine and provide the depolarizing & here AP still generates depolarizing currents -> why doesn’t AP force for the next 10 nodes; this is good b/c if some nodes go backwards from where it was generated? are poisoned (before the furthest one) -> current would skip o Answer: AP can’t turn around b/c membrane area before these poisoned nodes to next healthy node (you have to has entered its refractory period (Voltage-gated Na+ destroy a large part of axon to stop AP) channels are inactivated) -> this area cannot generate AP; Unmyelinated axons: these are regions on the axons that don’t so AP can only go down axon have multiple layers of myelin sheath -> current leakage & slowed o NOTE: AP still moves backwards, but b/c the Na+ channels conductance velocity; NOTE: they still have some insulation are inactivated, AP moving backwards just dies (Schwann cells & Oligodendrocytes engulf ~5-30 axons w/o Synapse: functional unit of a neuron w/ another neuron/ winding several times-> Remark Bundle effector organs (muscle/gland) o Small diameter & low membrane resistance -> slowed o Electrical synapse: type of synapse that doesn’t req. conductance velocity (dist. travelled by AP over time) release of neurotransmitters to send messages b/c they o NOTE: these areas have Na+ & K+ Voltage-gated channels have gap junctions made from connexin proteins that mixed allow small ions & depolarization to cross from membrane o NOTE: majority of axons are unmyelinated (cytosol) -> membrane (cytosol); used for rapid o Conduction of myelinated ~80m/s & unmyelinated ~2m/s communication like in the heart o Chemical synapse: type of synapse where neurotransmitters ARE REQ. & released in extracellular space b/t synapse (synaptic cleft, ~200 Å wide) -> bind to specific protein receptors on postsynaptic membrane NOTE: Synapse is presynaptic membrane (bouton containing vesicles filled w/ neurotransmitters) & postsynaptic membrane (dendritic membrane of receiving neuron) Axon terminal has boutons w/ vesicles o Vesicles are organelles containing neurotransmitters to be released into synaptic cleft via exocytosis How does vesicle release occur? 1. AP depolarizes axon terminal 2. Depolarization causes bouton membrane to reach -50mV -> Voltage-gated Ca2+ channels open -> Ca2+ enters the cell 3. Ca2+ entry triggers exocytosis of synaptic vesicles contents (Kiss & Run = transient OR Full Fusion = all transmitters are released) 4. Neurotransmitters diffuse across synaptic cleft & binds w/ receptors on postsynaptic membrane 5. Binding triggers a response in postsynaptic cell o Normally, vesicles are docked near presynaptic membrane in prep. for fusion w/ membrane; there are specific set of vesicles that are line-ed & ready to exocytosis o NOTE: vesicle release is probabilistic (by chance): 1 AP has 10-90%GMT This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:07:20 chance -05:00of releasing 1 vesicle Chemical synapses are processing stations for signals https://www.coursehero.com/file/119194231/Lec3-Action-Potential-Conductionpdf/ Powered by TCPDF (www.tcpdf.org) Lecture 4: Synaptic Potentials: Ionotropic & Metabotropic Post-Synaptic Receptors Neurotransmitters diffuse across synaptic cleft -> binds to specific site on receptor protein embedded in postsynaptic membrane o This binding causes conformation change of the post-synaptic receptor protein Receptors can be: (1) Ionotropic (directly open channels) OR (2) Metabotropic (initiates metabolic cascade to activate an enzyme) NOTE: RECEPTOR DETERMINES THE EFFECT, NOT THE TRANSMITTER Metabotropic receptor: binding of ligand to post-synaptic o You can have 1 transmitter bind to 2 diff. receptors -> 2 diff metabotropic receptor -> activates enzyme (usually G-protein responses coupled) Ionotropic receptor: binding of ligand (neurotransmitter) opens o Enzyme activation results in ->↑ production or destruction an ion channel in the post-synaptic membrane -> changes of 2nd messengers (cAMP, cGMP, or InP3 (Inositol postsynaptic MP (Post-Synaptic Potential or PSP) Triphosphate)) -> 2nd messengers activate other enzymes o PSP lasts ~20-40ms (as long as the transmitters are (ex. phosphokinases: phosphorylate membrane/cytosolic present) proteins) o When binding of ligand results in opening ion channels that o NOTE: phosphorylation of membrane proteins (ex. Ion results in depolarization (cations: Na+, K+) -> Excitatory PSP channels) -> results in modulation of ion currents or EPSP o Slower activation b/c req. 2nd messenger/activation of o When binding of ligand results in opening ion channels that other enzymes & influencing ion channels via metabolic results in hyperpolarizing (ions: Cl-, K+) -> Inhibitory PSP or effect (ex. Phosphorylation) will change MP very slowly -> IPSP slow EPSP/IPSP o Ex. Nicotinic receptor for Acetylcholine (Ach) o Ex. β-Adrenoreceptor is metabolic receptor for ▪ Ach binds to nicotinic receptors -> cation channels open Noradrenalin (NA) -> depolarization & EPSP occurs ▪ Binding of NA to β-Adrenoreceptor -> activates ▪ can be affected by nicotine (hence the name) -> adenylyl cyclase via G-protein alteration -> ↑ contributes to alertness, wakefulness, learning & production of cAMP -> activates kinases to memory, & Alzheimer’s phosphorylate membrane Ca2+ channels -> opens o Main ligands that act on ionotropic receptors: Ach, Ca2+ channels -> ↑ Ca2+ influx Glutamate, GABA, & Glycine (remember these ligands can ▪ Important for heart muscle; ↑ contractility still act on metabotropic receptors; it’s the receptor that ▪ β-blockers: blocks interaction b/t NA w/ its determines the effect, not the ligand) receptor -> ↓Ca2+ influx -> ↓contractility; used to ▪ GABA -> ↓excitatory signals b/t neurons -> induces prevent excessive activity of heart calming effect; Benzodiazepine is common drug for o Main ligands that act on metabotropic receptors: Ach anxiety b/c its ↑ effect of GABA -> inducing anti-anxiety (Muscarinic receptor), peptides (substance B, β- properties endorphin, ADH), catecholamines (noradrenaline, o Faster/immediate effect b/c open ion channel directly -> Fast dopamine), serotonin, purines (adenosine, ATP), gases EPSP/IPSP (NO, CO) Spread of PSPs PSPs are generated un unexcitable membrane (neuronal dendrites & cell bodies -> these areas don’t have high [ ] of Voltage-gated Na+ channels) -> thus, they can NOT generate AP o However, binding of transmitter -> generates EPSP (graded potential) -> EPSP MUST spread via passive conduction (b/c there is no Na+ channels) across cell body to trigger zone -> enough depolarization for trigger zone to reach threshold potential -> AP is generates & sent down axon o NOTE: graded potentials are not as strong as APs so they lose voltage over short distances easily as well as they have to travel through the cell body (has lots of organelles -> increases resistivity) This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:07:40 GMT -05:00 o NOTE: the nearest excitable membrane is beginning of axon (trigger zone) https://www.coursehero.com/file/119194027/Lec4-Synaptic-Potentials-Ionotropic-0-Metabotropicpdf/  PSP Summations Since biological tissue has poor conductivity -> loss of current/potential before reaching trigger zone -> trigger zone can’t reach threshold potential -> no AP o To fix this we need more EPSP (via summation) to depolarize trigger zone to -55mV o NOTE: you can add EPSPs/ IPSPs b/c they are not APs Spatial summation: min. 10-30 synchronous EPSPs from multiple synapses -> 1 dendritic tree o NOTE: ALL EPSPs MUST BE ACTIVATED @ SAME TIME Temporal summation: few active synapse each generating EPSPs @ high freq.; summated potentials reach threshold over period of time o Since EPSPs last ~ 30-40ms before dying out, then we can have successive input on a synapse to generate successive EPSPs to add on pre-existing EPSPs (like a staircase) Inhibitory Post-Synaptic Potential IPSPs are strategically places ½ way b/t where EPSPs are generated & trigger zone; located on cell soma o B/c of this, they can shut down EPSP currents before they reach the trigger zone -> preventing generation of AP Generating Spike Train How does it do this? o IPSP involves opening Voltage-gated Cl- channels (ECl- is How do we translate a long-lasting stimulus (~500ms) to the very close to resting MP (-70mV)) brain? By using a Spike Train o This means @ rest, open of Cl- channels would result in o We know that after an AP, Na+ are inactivated (refractory little change; however, when membrane is depolarized period) -> thus, we can’t generate another AP until the from EPSP -> Cl- channels will open -> forcing MP to go membrane repolarizes down to -70mV (clamping it) o So, we can just hyperpolarize the membrane after each o Essentially by preventing depolarization -> prevent spike quickly to restore Na+ channels to generate another excitation -> inhibitory effect which is what IPSPs do AP o NOTE: remember that Cl- ions are [ ]ed extracellularly; so After-Hyperpolarization is caused by Voltage-gated K+ when Cl- channels open, there is an influx of Cl- ions-> channels @ trigger zone polarizes or keeps MP @ -70mV o Hyperpolarization makes sure that after each spike Na+ IPSPs in NS generally play the role of controlling info b/c IPSPs channels reconfigure & the membrane is excitable again are more accurate than EPSPs o After hyperpolarization fades away -> Voltage-gated K+ channels close slowly -> MP will reach threshold thanks to EPSP -> new AP generated -> cycle repeats until long- lasting stimulus disappears This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:07:40 GMT -05:00 https://www.coursehero.com/file/119194027/Lec4-Synaptic-Potentials-Ionotropic-0-Metabotropicpdf/ Powered by TCPDF (www.tcpdf.org) Lecture 5: Receptor Potential, Adaptation; Peripheral/Central Nervous System Receptor Potential Is when there is a change in MP due b/c of receiving a signal from exterior sensory cue (ex. touch, light, heat) o Energy from environment will react w/ membrane proteins -> generally will cause depolarization (like EPSPs) o Exception: photoreceptors hyperpolarize after receiving energy from environment Receptor proteins are embedded in sensory cell membrane o They change conformation when specific amt of energy is received & depolarize the membrane o When receptor changes conformation it can -> 1. Directly open ion channels: Ex. cation channels -> depolarizes the membrane (like ionotropic pathway) 2. Enzyme is activated via G-protein coupling -> leads to production of 2nd messenger (cAMP, cGMP, InP3) -> induces more of 2nd messengers -> amplifying the signal; (like metabotropic) o Metabotropic pathway: chemical stimulus binds to specific metabotropic receptor (G-protein coupled) -> activated G-protein -> activates adjacent enzyme adenyl cyclase -> produces 2nd messenger (cAMP) -> cAMP activates kinases -> directly interacts w/ ion channels or phosphorylates other proteins ▪ Pro -> 2 stages of amplification: (1) G-protein can activate # of diff. enzyme molecules (1/+) & (2) each of these enzymes or proteins can separately produce more 2nd messengers (cAMP) ▪ Therefore, 1 stimulus can produce lots of cAMP -> amplification of signal Receptor protein: Olfactory receptor o These are specific receptor proteins that bind to specific odorant (chemical stimuli) -> activate G-protein -> activate adenyl cyclase -> produces cAMP -> cAMP binds to ion channels -> allow influx of cations (Na+ & Ca2+) -> depolarization of the membrane -> graded potentials are fired -> graded potentials are passively conducted to trigger zone -> fires AP to reach -> olfactory bulb -> olfactory tract -> olfactory cortex o When small signals are amplified -> induces ↑ sensitivity in olfactory cells -> this allows olfactory receptors to be activated 2. Sensory cell can release vesicle when depolarized; by 1 or 2 molecules impulses are generated in post-synaptic neuron: Sensory Cell Transmission: o Ex. Taste Receptor: chemical stimulus -> activated 1. Sensory cell generates an AP @ spike-generating zone receptors induce depolarization of membrane -> (excitable membrane): depolarizing current travels through membrane via o @ the sensory cell axon terminal, the receptor potential passive conduction -> current reaches other end of (depolarizing current) has to travel via passive conduction & taste sensory cell -> membrane is depolarized generate summation @ branch point to reach threshold -> sufficiently -> causes Ca2+ influx -> triggers exocytosis generate AP of vesicles (not producing AP) o NOTE: branch point is usually the first patch of excitable o NOTE: 2nd neuron must produce AP based on sensory membrane This study source (Voltage-gated was downloaded Na+ channels) by 100000818475141 -> allows generation from CourseHero.com of 22:08:12 GMTcells on 10-03-2024 signals (released molecules from exocytosis of -05:00 AP vesicles) https://www.coursehero.com/file/119194008/Lec5-Receptor-PotentialsJ-Adaptation-Peripheral-Central-Nervous-Systempdf/  Adaptation: when MP begins decaying over time o Original voltage is not sustained & dropped over time, despite constant stimulus o Slowly adapting: receptor potential sustained for duration of stimulus; interested in overall magnitude of stimulus; as long as there is a stimulus that is maintained -> there will be some receptor potential o Rapidly adapting: receptor potential induced by change in stimulus energy; decays to 0 when stimulus Coding for Modality intensity is constant; interested in how quickly stimulus How do we distinguish b/t diff. types of stimulus? (Ex. colors) is being delivered (velocity) Solution: we use Labelled Line strategy -> devote one pathway to a ▪ Addition of stimulus -> +ive receptor potential particular stimulus & activity in this pathway codes particular spike & removal of stimulus -> -ive receptor stimulus quality; other qualities have other sys./pathways potential spike (hyperpolarization) associated w/ them ▪ Ex. Pacinian corpuscles are rapid adapting All sensations have sub-modalities to be distinguished -> devising receptors -> senses vibration, pressure & touch receptor proteins or pathways for each of these won’t be efficient & ▪ Nociceptors don’t adapt to pain sensation very would take up too much space -> is there a better way? Solution: well -> this is why pain management is difficult Population Code -> codes based on ratio of activity from restricted Habituation: progressively weaker responses to successive # of diff. receptor types or population of receptors (more than 1 stimuli over time receptor is used) o Depends on cell type, some will show large degree & o A given receptor (e.g. A), type will respond to a wide range, but some won’t it has a peak and that is different from others o NOTE: if there is large time delays b/t successive o Thus, any given stimulus (dotted line) will activate one stimuli -> habituation won’t occur receptor (C) very strongly but others (A, B) more weakly Coding of Stimulus Intensity Receptive Field To code for stimulus intensity we can use varying receptor Receptive Field: Each sensory neuron responds to particular spatial potentials area; territory in which neuron can get activated o For greater stimulus intensity -> greater change o NOTE: Receptive Field always defined in relation to a given receptor depolarization (graded potential) -> more neuron and each sensory neuron will have diff. Receptive transmitter released &/or higher AP freq. generated Field o Greater the depolarization -> faster membrane brought o ~10-20 mm across; in fingertips it is less -> ~1 mm across up from hyperpolarization to generate new AP -> more sensitive b/c receptive field is smaller o NOTE: Impulse frequency is always limited by refractory period (1000 AP/sec) -> what if you want to code above this limit? Solution: use more neurons o As stimulus intensity increases -> recruit higher threshold sensory neurons -> req. higher stimulus to generate a receptor potential ▪ Ex. Receptor A reaches max. discharge rate of 1000 AP/sec, but with higher stimulus intensity, we can recruit Receptor B, a receptor w/ a higher threshold ▪ NOTE: Receptor A is more sensitive to stimuli than Receptor B This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:08:12 GMT -05:00 https://www.coursehero.com/file/119194008/Lec5-Receptor-PotentialsJ-Adaptation-Peripheral-Central-Nervous-Systempdf/ Powered by TCPDF (www.tcpdf.org) Lecture 6: Blood Brain Barrier & CSF Blood Brain Barrier The brain & spinal cord are protected from the general blood circulation & the body Ionic composition of the ECF around neuron has to be controlled o Can’t change excitability of the membrane or then similar effects w/ injection of KCl will occur -> no more production of AP o Can’t have neurotransmitters floating around -> may excite neurons that aren’t supposed to be excited BBB regulates the ECF in the brain & spinal cord 1 wall of the BBB exists b/t the blood vessels & the interstitial fluid and another wall exists b/t the blood vessels & the CSF (ventricles) o NOTE: there is no wall (or non-barrier) b/t the interstitial fluid Brain Encasings & CSF (ventricles) -> free diffusion of chem. -> these are o 1st line of defense is the skull -> very durable essentially made of the same composition o Meninges (brain & spinal) includes Focus: Parkinson’ disease o Dura mater: very tough membrane sac containing the o Caused by lack of dopamine in the brain -> muscle stiffness & brain & the spinal cord; superficial sustained muscles contraction (dystonia) -> twitching o Arachnoid membrane: much more delicate tissue o B/c of BBB -> normal injection of dopamine doesn’t get to brain o Pia mater: lies right on top of the brain & titrated to from general circulation arachnoid by arachnoid trabeculae; deep o Solution: L-Dopa (dopamine pre-cursor) -> can cross BBB -> o Subarachnoid space: b/t the arachnoid membrane & pia then is converted to dopamine once it enters the brain mater; filled w/ CSP -> allows brain to float & be protected o NOTE: dopamine is involved in the rewards pathway from mechanical stress (cushion); CSF is not compressible Focus: MSG & doesn’t act like cushion but membranes surrounding act o MSG or monosodium glutamate -> causes thirst & stiff neck like cushion b/c they can stretch & move o This is b/c MSG can’t cross BBB -> can’t gain access to brain o Meningitis -> infection in the meninges but instead activate glutamate receptors outside the brain Reticular formation: loose nerve cells that connect brain w/ (PNS) mainly @ the neck behavior (b/t brain & spinal cord) Areas Lacking BBB: most of the brain is protected by the BBB, but it o If you punch someone in the jaw @ correct angle -> is not con. b/c it is essential in some areas of the brain for neurons reticular formation may vibrate -> passing out to communicate freely w/ the blood stream (ex. Hypothalamus) o Wearing teeth guards reduces this by absorbing vibrations o The hypothalamus releases neurosecretory hormones that In subarachnoid space there are blood vessels -> capillaries to must pass through capillaries to reach the pituitary gland -> the brain tissue -> BBB in b/t the capillaries & brain tissue to thus, BBB is purposely broken to allow communication b/t monitor passage of metabolites these 2 important brain struc. o The endothelial lining of the BV, mostly contains large gaps o In Circumventricular organs (around 3rd ventricle) the BBB is (fenestrations) trough which molecules can pass broken so neurons can sense specific chem. [ ] o In the brain, endothelial cells are tightly bound leaving no o Generally, BBB is broken where interactions b/t endocrine gaps -> this makes the BBB (everything must go through system is needed/ req. sensitivity to [ ] of metabolites in the vessels; nothing an exit the vessels) plasma This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:08:21 GMT -05:00 https://www.coursehero.com/file/119194023/Lec6-Blood-Brain-Barrier-0-CSFpdf/  Ventricles Ventricles: are cavities deep inside the brain o Lateral Ventricle (LV) is a large curving struc. inside each cerebral hemisphere, paired across the midline o 3rd Ventricle is right in the middle, deep in the brain under the cerebral hemisphere o Aqueduct of Sylvius is a channel that 3rd ventricle uses to communicate w/ 4th ventricle o 4th Ventricle is below the 3rd ventricle o Central Canal: canal that connects 4th ventricle w/ middle of spinal cord o NOTE: All ventricles are filled w/ CSF & there is a con. connection b/t all ventricles & chambers Astrocytes CSF produced in the ventricle drains through the ventricle of the central canal Walls of capillaries are lined w/ ‘end feet’ of glial cells o CSF then moves to outer parts of brain (subarachnoid space) (astrocytes) & exits @ top of brain into large venous sinus (on the midline) Provides bridge b/t neurons & blood vessels -> CSF can go back into general circulation Are efficient @ glycolysis -> produce lactate as end-product -> o Thus all the CSF eventually drains into either venous/veins neurons can use lactate as substrate for ATP production -> somewhere along the line produces ATP more efficiently Arachnoid villi: allows ½ of CSF to drain into venous sys. They remove neurotransmitter b/c 1 feet is @ synapse of neurons o It is an out pouching of the arachnoid tissue -> sticks out Follow & latch onto BV (some end feet latched onto the BV & the through the dura mater into venous sinus -> CSF drains into other w/ neurons) the venous sys. Local Blood Flow: o Drains w/o pump o Astrocytes can regulate local blood flow b/c they are Ventricles filled w/ CSF -> bathing medium of brain (very regulated located where the BV are -> can signal when to ionic content & few macromolecules) dilate/constrict (increase/decrease blood flow) o CSF made from plasma by choroid plexus -> lines ventricles o Astrocytes have connections w/ neuron @ synapse & when (LV, 3rd, 4th) they detect increased signaling (lots of activity) -> they can o All ventricles filled w/ CSF (including subarachnoid space b/c send a metabolic signal outward to BV (opposite to nutrient of communication b/t ventricles & subarachnoid space) & flow), signaling neuronal activity level eventually drains into venous sys. o Glutamate (neurotransmitter) is released in synapses -> o CSF is made & drained con. (moves fluid w/o pump) -> allows triggers Ca2+ release w/in astrocytes -> Ca2+ wave travels for cleansing through astrocytes & triggers prostaglandin (PGE2) Choroid plexus: produces CSF con. (550ml/day) to circulate -> is release @ end-foot -> BV cleansing mech. ▪ NOTE: PGE2 causes vasodilation -> increased blood o Produces most CSP (not all b/c capillaries produce it also) flow o Made up of epithelial cells connected by tight junctions; dense network of capillaries ballooning out into the ventricular wall w/ tight junction -> everything must move through the capillaries CSF o Is produced by choroid plexus in ventricles o Fills ventricles & subarachnoid space o Has same osmolarity & [Na+] as blood o Very less [K+], [Ca2+], & [Mg2+] -> similar to interstitial fluid bathing neurons o Total volume on avg. = 215mL; CSF is replaced 3x/day o Cranial CSF is 140 mL (25mL -> ventricles, 115mL in subarachnoid space) & spinal CSF is 75mL ▪ Thus, most of CSF is in subarachnoid space -> cushion o Lumbar puncture (spinal tap) is diagnostic, therapeutic This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:08:21 GMT -05:00 procedure -> collect sample of CSF for analysis (infections) https://www.coursehero.com/file/119194023/Lec6-Blood-Brain-Barrier-0-CSFpdf/ Powered by TCPDF (www.tcpdf.org)  Lecture 7: Endocrine Principles Homeostasis Homeostasis isn’t equilibrium instead it refers to the stability of the body’s internal environment o Ex. ECF & ICF have varying [ ]s of the diff. ions -> they are not in equilibrium in relative to each other; allows flow b/t ECF & ICF (important for neurons) o The state of homeostasis is when the composition of the body’s compartments are relatively stable -> AKA dynamic steady state ▪ ‘dynamic’ b/c the molecules are still moving b/t 2 compartments, but @ the same time keeping homeostasis Setpoint: is the optimum value in a control system (ex. Temp, [ ]s, pressure etc.) o Control sys. in our body don’t stay @ the specified setpoint & instead may deviate b/t a range around the setpoint +/- o If ever out of range -> the control sys. will respond Negative feedback vs. Positive feedback appropriately o In the fish tank example below: the response loop Negative feedback: the initial stimulus -> creates a response -> decrease turns on when the temp. is colder than the lower the stimulus -> results in response loop shutting off; creates a stabilizing bound of the setpoint range & negative feedback is effect what turns off the response loop once the temp. o Ex. Regulation of cortisol secretion: when enough cortisol is reaches the high bound of the setpoint range released -> cortisol negatively feedbacks on CRH release & ACTH Control systems are made of 3 things: release -> prevents further secretion of cortisol (you don’t need o Input signal: can be a stimulus (external or anymore) internal), but it starts the sys. o When you need more cortisol again, the negative feedback loop is o Integrating center: integrates incoming lifted -> allows cortisol it increase its [ ]s again information -> creates appropriate response; uses Positive feedback: the initial stimulus -> creates a response -> increases feedback control to maintain the homeostasis the stimulus -> more response -> increases stimulus further; an external o Output signal: creates a response under control of factor is req. to shut off the positive feedback loop; NOTE: this loop moves the integrating center AWAY FROM HOMEOSTASIS o Ex. Fish tank temperature o Ex. Oxytocin & control of uterine contractions: When the baby (1) Stimulus: Water temp. below setpoint drops in uterus to start labor -> cervical stretch (initial stimulus) -> (2) Sensor/receptor: thermometer senses temp in response, oxytocin is released -> uterine to contract -> further decrease pushes baby against cervix -> more cervical stretch (3) Afferent pathway: signal passes from sensor o Eventually the cycle stops once the baby is delivered to control box via wire (4) Integrating center: control box is programmed to respond to temp. below 29 degrees (5) Efferent pathway: signal passes via wire to heater (6) Target/effector: heater turns on (7) Response: water temp. increases (8) Thermometer senses when water is back @ set point -> integrating center turns off sys. This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:08:49 GMT -05:00 https://www.coursehero.com/file/119194100/Lec7-Endrocrine-Principlespdf/ Cell-cell communication (Local communication) Simple & Complex Reflexes Gap junctions: protein bridges b/t adjacent cells that allow Simple (or local) reflex: mediated by nervous/endocrine sys. NOT cytoplasm to flow b/t the connected cells BOTH o Made of connexins (membrane-spanning protein) that o Ex. Local change in blood vessels -> cells in local vicinity joined together to make connexons which can open & close initiate local response o Small ions & molecules move through these (ex. ATP, cAMP) o NOTE: usually no integrating center involved o Important for cardiac muscle Complex reflex: mediated by BOTH nervous & endocrine sys.; goes Contact-dependent: req. interaction b/t membrane-bound through many integrating sys. molecules on 2 cells; 1 surface molecule on 1 cell binds to o Ex. Systemic change in blood pressure (huge stimulus) -> membrane protein of another cell change is sensed near the brain -> brain evaluates change & o Important for immune system initiates response (integrating center) -> response is initiated Autocrine: molecules act on same cell that secreted them & @ a distant site Paracrine: molecules are secreted by 1 cell & diffuse to adjacent o NOTE: the brain is very far away -> “long reflex” cells Homeostatic reflex pathways req. sensors to detect change o Molecules move through interstitial fluid; short dist. o Central receptors: in/close to brain (ex. Eyes, ears etc.) (limited) o Peripheral receptors: outside of brain(ex. Chemoreceptors, o Ex. Histamine osmoreceptors etc.) o Cellular receptors Long-distance communication Long-distance signaling may be electrical signals passing along neurons/chemical signals that travel via circulatory sys./both o Nervous sys: electrical signal (AP) is sent down neuron -> causes release of neurotransmitters (chem. that diffuse across small gap to target cell) -> bind to target cell -> induces response o Endocrine sys: Endocrine cells release hormones (affect target cells w/ corresponding-hormone receptors only) -> hormones enter blood stream -> reach area w/ target cell -> induces response o Neuroendocrine sys: electrical signal sent down neuron -> causes release of neurohormones (chem. released to blood for action @ distant targets) -> enter blood stream -> affect target cells w/ corresponding receptors only -> induces response This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:08:49 GMT -05:00 https://www.coursehero.com/file/119194100/Lec7-Endrocrine-Principlespdf/  Endocrine system Exocrine: substances secreted to environment external to self (ex. Sweat & digestive enzyme); into duct Endocrine: hormones secreted into the bloodstream; into the bloodstream Features of hormones o Can be made in diff. places in body o Chem. made by cells in specific endocrine glands or other tissues o Transported in the blood to distant targets o Bind to specific receptors o May act in multiple tissues o Alter activity of target cells o Action must be terminated o Maintain homeostasis/precipitate change in many physiological processes How were hormones identified? Based on 1849 experiment by the German physiologist Arnold Adolph Berthold o Remove glands & observe results o Replace gland o Replace extract from gland o Give excess gland (or extract) o Purify extract & test in biological assay This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:08:49 GMT -05:00 https://www.coursehero.com/file/119194100/Lec7-Endrocrine-Principlespdf/ Powered by TCPDF (www.tcpdf.org) Lecture 8: Hormones Classification of Hormones Hydrophilic hormones o Water soluble -> dissolvable in plasma o Not lipid soluble (lipophobic) -> CAN’T cross plasma membrane o Synthesized in advanced & stored in vesicles -> released via exocytosis b/c can’t move across membrane o Ex. Peptide hormones, protein hormones & catecholamines Hydrophobic hormones o Not water soluble, can’t dissolve in plasma o Lipid soluble (lipophilic) -> CAN cross plasma membrane o Synthesized on demand b/c they can ‘leak’ out of the cell b/c they are lipid soluble -> released via simple diffusion -> when moving the blood they have carrier proteins to transport these hydrophobic hormones o Ex. Steroid & thyroid hormones NOTE: plasma is made of mainly water Peptide/protein hormones: range from small peptides of 3 AAs to large proteins & glycoproteins o Most hormones are placed in this category, made in advance, synthesized like secreted proteins, stored in vesicles (see steps below), released by exocytosis upon signal, water soluble o Short-half life in plasma o Bind to membrane receptors -> in order for signal to get into cell o Synthesis is like how normal proteins are made: (1) first comes from ribosome as inactive protein called preprohormone (contains 1/+ copies of peptide hormone, signal sequence & other peptide seq.) (2) inactive preprohormone moves through ER -> signal sequence is cleaved -> smaller still-inactive molecule now called prohormone (3) Transport vesicle pinches off of the ER -> moves to Golgi (4) @ Golgi prohormone is packed in secretory vesicle w/ proteolytic enzymes that cut prohormone into active hormone & other fragments (process of post-translational Steroid hormones: derived from cholesterol (parent molecule) modification) o Made on demand (b/c hydrophobic & can leak thro (5) The secretory vesicle remains in the cytoplasm of endocrine membrane), not stored in vesicles & made when needed, cell until cell receives signal for secretion released from cell by simple diffusion, water insoluble (6) Once release signal is received by endocrine cell -> vesicles (bound to carriers in blood) move to cell membrane & release contents by exocytosis o Long half-life in plasma b/c bound to carrier proteins (calcium-dependent) o Diffuse into target cells/taken up by endocytosis of o Single preprohormone can contain several copes of the SAME steroid hormones carrier proteins HORMONE or DIFFERENT TYPES OF HORMONES (genes can code o Cytoplasm/nucleus receptors -> effects transcription & for multiple diff. hormones) acts transcription factor (but can also act on plasma o Active peptides released depends on specific proteolytic membrane receptors) processing enzymes & the cell type of the endocrine cell o Depending on where the cholesterol is found (cell type) -> o Ex. Proinsulin -> insulin: through the process of post- there will be formation of diff. steroid hormones b/c of translational modification -> active insulin & C-peptide is presence of diff. enzymes in organ/cell type; estrogen in released; B/c of the proportionality b/t C-peptide [ ]s & active ovaries & aldosterone/cortisol in adrenal cortex insulin This study source was[ downloaded ]s in the blood -> doctors use from by 100000818475141 C-peptide o GMT levels to on 10-03-2024 22:08:56 CourseHero.com Cells-05:00 that secrete steroid hormones have usually large measure how much insulin is in the blood amount of ER (where steroid are synthesized) https://www.coursehero.com/file/119194258/Lec8-Hormonespdf/  Control of hormone release Amine hormones: derived from single AAs (Trp/Tyr) o Trp derivatives: Melatonin (behaves like peptides/steroids & Endocrine cells directly sense stimuli, then secrete hormones Tyr derivatives: Catecholamines (behave like peptides) & How do the stimuli trigger hormone release? -> Act through Thyroid hormones (behave like steroids) intracellular pathways to: o Melatonin: secreted @ night -> controls circadian rhythm & o Change membrane potential via movement of ions made in pineal gland o Increase free cytosolic Ca2+ ▪ Diverse effects: transmits info (light-dark cycles to o Change enzymatic activity govern biological clock), immune modulation, anti-oxidant o Increase the transport of hormone substrates into the cell o Depending on which cell type/organ Trp/Try is found in -> the o Alter transcription of genes coding for hormones or for structure of the amine hormone will be diff -> therefore have enzymes needed for hormone synthesis diff. func. o Promote survival & in some cases growth of the endocrine o Synthesizing catecholamines cell ▪ Made in adrenal medulla (middle of adrenal gland) mainly Ex. Glucose stimulation of insulin release in cytosol (1) Increasing glucose in the blood -> binds to GLUT2 receptor ▪ Stores in vesicles prior to release (2) Signaling cascade increases ATP in the cell -> changes ratio ▪ Released via exocytosis of ATP:ADP ▪ Lipophobic, water soluble (3) Increases in cytosolic ATP -> binds to K+ channel -> blocks it ▪ Bind to membrane receptors -> reduces flow of K+ ions from beta cells -> depolarizes cell (4) Depolarization of K+ channels lead to opening of voltage- gated Ca2+ channels (5) Influx of Ca2+ ions is a signal for the vesicles to exocytosis insulin Hormones released from the hypothalamus & anterior pituitary regulate the release of several hormones o Main system: hypothalamus makes hypothalamic hormone - > anterior pituitary in response makes anterior pituitary hormone -> peripheral endocrine gland in response makes another hormone -> this hormone effects target cell/organ o There is -ive feedback loop w/ the final hormone on -> anterior pituitary & hypothalamus & the anterior pituitary hormone on hypothalamus o Hypothalamic releasing & inhibiting hormones o NOTE: posterior pituitary can’t make hormones but can induce release of them Hormone interactions: most cells sensitive to more than one hormone & exhibit interactive effects o Synergistic effects: multiple hormones act together for greater effect; EX. FSH & testosterone on sperm production o Permissive effects: 1 hormone enhances the target organ’s response to a 2nd later hormone (needs release of 1st hormone to allow 2nd hormone to work); Ex. Estrogen prepares uterus for action of progesterone o Antagonistic effects: 1 hormone opposes the action of another; Ex. Insulin lowers blood glucose & glucagon raises it This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:08:56 GMT -05:00 https://www.coursehero.com/file/119194258/Lec8-Hormonespdf/ Powered by TCPDF (www.tcpdf.org) Lecture 9: Receptors & Signaling Receptors Hormone binds to receptor -> induces change in conformation & activity of the receptor -> effects the activity of intracellular signaling pathways -> this can lead to synthesis of target protein &/or Hormones & Signaling modification of existing target proteins What are the common characteristics of receptors? 2 main receptors: o Large proteins; categorized in families o Intracellular receptors (bind lipid soluble o Can be multiple receptors for 1 ligand/more than 1 ligands for 1 hormones): receptor ▪ Located in the cytosol &/or in the nucleus o There can be a variable number of them in a target cell ▪ Directly alter gene transcription = genomic effects o Can be activated/inhibited ▪ Process: o Located in cell membrane, cytoplasm, nucleus (1) Lipophilic messenger diffusion through the Receptors are saturable: meaning that all of the receptors can membrane of target cell reach full capacity (2) Messenger can either bind to cytoplasmic o Ex. As the [ ]s of testosterone increases -> more testosterone receptor -> goes to nucleus & binds to hormone binds to the receptors response element OR messenger binds to o Up to a certain point the amount of bound testosterone begins to nuclear receptor -> binds to hormone level off b/c there are no more receptors left ->all receptors response element are saturated w/ testosterone (3) mRNA is transcribed in response o Properties of receptors: High affinity, saturable, specific & (4) mRNA is translated to protein in cytosol by reversible ribosome ▪ Hormone response elements are specific DNA seq. o Plasma membrane receptors ▪ G protein-coupled receptors: Ligand binding to a G protein-coupled receptor opens an ion channel/alters enzyme activity ▪ Receptor-enzyme receptors: Ligand binding to a receptor-enzyme activates an intracellular enzyme ▪ Receptor-channel: Ligand binding opens/closes the channel ▪ Integrin receptor: Ligand binding to integrin receptors alters enzymes/cytoskeleton ▪ NOTE: the bolded receptors are ones that we are focusing on in PSL300 Hormone response elements are specific DNA seq. o Sometimes receptors recruits co-repressors to inhibit transcription o Only genes w/ the response elements will be activated/repressed Peptide hormones o Can’t penetrate target cell o Bind to surface receptors & activate intracellular processes through second messengers Steroid hormones o Penetrate plasma membrane & bind to internal receptors (usually in nucleus) o Influence expression of genes of target cell Take-05:00 o GMT This study source was downloaded by 100000818475141 from CourseHero.com on 10-03-2024 22:09:05 several hours-days to show effect due to lag for protein synthesis https://www.coursehero.com/file/119193909/Lec9-Receptors-and-Signalingpdf/  Hormones & Signaling con. o Process of Gaq proteins: target -> phospholipase C (1) Messenger binds to Gaq protein-coupled receptor (GPCR) Receptor-channel process which activates the G protein & the q subunit of the alpha