Lecture 17 > Flashcards
Lecture 1: Membranes, ions & potentials
Objectives:
- Review the generation of the resting membrane potential
- Review the generation of the action potential
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Membrane ion pumps generate an .. … and a …. …. across the membrane
Excitable cells, including neurons, can rapidly change this … …. and thus use it to carry information
Membrane ion pumps generate an ION GRADIENT and a VOLTAGE DIFFERENCE across the membrane
Excitable cells, including neurons, can rapidly change this MEMBRANE POTENTIAL and thus use it to carry information
The resting membrane potential
- Membrane pumps set up .. ….
- The membrane has .. & … channels
- Most Na+ channels are … at rest
- Specific K+ channels (leak channels) remain … at rest
- K+ ions flow … of the cell
The resting membrane potential
- Membrane pumps set up ION GRADIENTS
- The membrane has Na+ & K+ channels
- Most Na+ channels are CLOSED at rest
- Specific K+ channels (leak channels) remain OPEN at rest
- K+ ions flow OUT of the cell
The resting membrane potential
- K+ equilibrium reach when … gradient drive …. is balanced by … drive ….
- This equilibrium potential for K+ is about ..mV
The resting membrane potential
- K+ equilibrium reach when CHEMICAL gradient drive OUT is balanced by ELECTRICAL drive IN
- This equilibrium potential for K+ is about -80mV
During the rising phase … enters - cell membrane rapidly …..
Membrane potential becomes …. because Na+ conductance exceeds that of K+
During the rising phase Na+ enters - cell membrane rapidly DEPOLARIZED
Membrane potential becomes POSITIVE because Na+ conductance exceeds that of K+
During the falling phase the voltage-gated Na+ channels have …
Delayed voltage gated K+ channels …
K+ leaves the cell causing …
During the falling phase the voltage-gated Na+ channels have CLOSED
Delayed voltage gated K+ channels OPEN
K+ leaves the cell causing RE-POLARIZATION
Undershoot because K+ conductance is …. membrane potential towards (-80mV) membrane becomes …. …. due to …..
Undershoot because K+ conductance is INCREASED membrane potential towards (-80mV) membrane becomes RELATIVE REFRACTORY due to HYPERPOLARIZATION
Na+ channels open upon depolarization but close again despite continued depolarization referred to as …. ….
Provides a period of … ….
Cannot be activated until …. to … ….
Na+ channels open upon depolarization but close again despite continued depolarization referred to as CHANNEL INACTIVATION
Provides a period of ABSOLUTE REFRACTION
Cannot be activated until RETURNED to RESTING POTENTIAL
Molecular analysis of the Na+ channels provides a model to describe its properties
Gate prevents Na+ flux at … … …
Gate opens upon …. (to -40mV)
… enters cell
Channel inactivated when …. portion of channel swings into pore
“plug” removed upon return to .. … …
Molecular analysis of the Na+ channels provides a model to describe its properties
Gate prevents Na+ flux at RESTING MEMBRANE POTENTIAL
Gate opens upon DEPOLARIZATION (to -40mV)
Na+ enters cell
Channel inactivated when GLOBULAR portion of channel swings into pore
“plug” removed upon return to RESTING MEMBRANE POTENTIAL
…. Binds to the outside of the channel and prevents it ….
TETRODOTOXIN Binds to the outside of the channel and prevents it OPENING
Lecture: Membranes, ions & potentials
Objectives
- What is a neurotransmitter vesicle and how is it handles at the synapse?
- What are the difference b/w SSV and LDCV?
- What are the roles of vesicle-associated proteins?
- What are mechanisms of neurotransmitter release?
- How does neurotransmitter release alter changes in stimulation strength?
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Presynaptic events
Summation may be …
- Multiple input neurons activated
Summation may be …
- Input neuron strongly activated
Presynaptic events
Summation may be SPATIAL
- Multiple input neurons activated
Summation may be TEMPORAL
- Input neuron strongly activated
Nerve terminals often contain two types of synaptic vesicle
- …. & ….
Nerve terminals often contain two types of synaptic vesicle
- SSV (small synaptic vesicles) & LDCV (secretory vesicles)
SSV contain … neurotransmitters (NT)
LDCV also contain …. NT an ….
LDCV more frequent in …. neurons or …. cells
SSV contain CLASSICAL neurotransmitters (NT)
LDCV also contain CLASSICAL NT an NEUROPEPTIDES
LDCV more frequent in NEUROSECRETORY neurons or NEUROENDOCRINE cells
LDCV
… precursors synthesized by …
packaged into vesicles by …
Delivered to nerve terminal by … …
… process en route
Vesicles position at …. release sites
LDCV
NEUROPEPTIDE precursors synthesized by ER
packaged into vesicles by GOLGI
Delivered to nerve terminal by AXONAL TRANSPORT
PEPTIDES process en route
Vesicles position at EXTRASYNAPTIC release sites
SSV
Vesicles synthesized by …
Delivered to nerve terminal by … …
enter … …
Become filled w/ .. …
SSV
Vesicles synthesized by GOLGI
Delivered to nerve terminal by AXONAL TRANSPORT
enter VESICLE CYCLE
Become filled w/ CLASSICAL NT
SSV
- may enter one of two … ….
- A reserve pool associated w/ …
A readily releasable or docked pool at … site
SSV
- may enter one of two VESICLE POOLS
- A reserve pool associated w/ CYTOSKELETON
A readily releasable or docked pool at ACTIVE site
SSV
Ca+ … through voltage-gated Ca2+ channels triggers … …
SSV membrane recycled by … to … or … … …
SSV
Ca+ INFLUX through voltage-gated Ca2+ channels triggers VESICLE EXOCYTOSIS
SSV membrane recycled by ENDOCYTOSIS to ENDOSOME or RESERVE VESICLE POOL
SSV
- Pumps to generate … gradients
- Used to power transporters to … ….
SSV
- Pumps to generate H+ gradients
- Used to power transporters to LOAD NEUROTRANSMITTERS
SSV
Small … binding proteins
Assist in vesicle … & …
Provide an on (..) or off (…) indicator of vesicle location
SSV
Small GTP binding proteins
Assist in vesicle TARGETING & DOCKING
Provide an on (GTP) or off (GDP) indicator of vesicle location
SSV
- …. proteins (synaptobrevin)
Bind to complementary …. on synaptic membrane
Assist in … vesicles and priming for …
SSV
- v-SNARE proteins (synaptobrevin)
Bind to complementary t-SNARES on synaptic membrane
Assist in DOCKING vesicles and priming for RELEASE
SSV
- Proteins comprising the … machine
- … sensor (synaptotagmin)
SSV
- Proteins comprising the EXOCYTOTIC machine
- … sensor (synaptotagmin)
SSV
- Proteins involved in endocytosis (…)
- And formation of coated pits (…)
SSV
- Proteins involved in endocytosis (DYNAMIN)
- And formation of coated pits (CLATHRIN)
SSV docking
As noted earlier requires interaction … proteins
…. involved in vesicle trafficking throughout the cell
But specific v-SNARE and t-SNARE pairs mediate … … …
SSV docking
As noted earlier requires interaction SNARE proteins
SNARE involved in vesicle trafficking throughout the cell
But specific v-SNARE and t-SNARE pairs mediate mediate SYNAPTIC VESICLE DOCKING
SSV docking
v-SNARE = …
t- SNARE = … & …
SSV docking
v-SNARE = SYNAPTOBREVIN
t- SNARE = SYNATAXIN & SNAP25
Synaptic vesicle fusion with membrane promoted by …. “….”
L2&3, page 35-37
Synaptic vesicle fusion with membrane promoted by SNARE “ZIPPING”
Vesicle protein … provides a mechanism for Ca2+ regulation
Vesicle protein SYNAPTOTAGMIN provides a mechanism for Ca2+ regulation
L2&3, page 47
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a-latrotoxin from the black widow spider interacts with a synaptic protein called …
Causes massive release of ….
but not …
a-latrotoxin from the black widow spider interacts with a synaptic protein called Neurexin
Causes massive release of SSV
but not LDCV
Objectives
- What is a neurotransmitter?
- How are neurotransmitters classified?
- How are neurotransmitter receptors classified
- How do neurotransmitters work?
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Classification of Neurotransmitters
Type I: … ….
- Glutamate (excitatory)
- Glycine and GABA (inhibitory)
Type II: … & ….
- Acetylcholine
- Catecholamines (noradrenaline & dopamine)
- ATP
- Histamine
Type III: - ….
- Opioids, substance P, vasoactive intestinal peptide
Type IV: - ….
- NO, CO
Classification of Neurotransmitters
Type I: AMINO ACIDS
- Glutamate (excitatory)
- Glycine and GABA (inhibitory)
Type II: AMINES & PURINES
- Acetylcholine
- Catecholamines (noradrenaline & dopamine)
- ATP
- Histamine
Type III: - NEUROPEPTIDES
- Opioids, substance P, vasoactive intestinal peptide
Type IV: - GASES
- NO, CO
Criteria for a neurotransmitter
- Present in the … terminal
- The enzymes for its synthesis exist in the …. terminal or … ….
- Released in response to nerve terminal ….
- Specific receptors exist on the ….. membrane
- Pharmacological agents should … or … neurotransmitter
Criteria for a neurotransmitter
- Present in the PRESYNAPTIC terminal
- The enzymes for its synthesis exist in the PRESYNAPTIC terminal or CELL BODY
- Released in response to nerve terminal DEPOLARIZATION
- Specific receptors exist on the POSTSYNAPTIC membrane
- Pharmacological agents should MIMIC or
INHIBIT neurotransmitter
Fast acting receptors (milliseconds)
- Have intrinsic .. … (ligand gated ion channels)
- Channel opens to allow … or … of ions
- … or … depending on ion involved and its direction of movement
Fast acting receptors (milliseconds)
- Have intrinsic ION CHANNELS (ligand gated ion channels)
- Channel opens to allow INFLUX or EFFLUX of ions
- EXCITATORY or INHIBITORY depending on ion involved and its direction of movement
Slow acting receptors (seconds)
- …. …. (metabotropic) receptors
- May have multiple actions (…. or …)
- Directly regulate .. ….
- Generate … …
- Thus regulate enzyme activity and … …
Slow acting receptors (seconds)
- G-PROTEIN COUPLED (metabotropic) receptors
- May have multiple actions (EXCITATORY or INHIBITORY)
- Directly regulate ION CHANNELS
- Generate SECOND MESSENGERS
- Thus regulate enzyme activity and GENE EXPRESSION
Acetylcholine
- ACh synthesized by … ….
- Following synaptic release Ach degraded by ….
Acetylcholine
- ACh synthesized by CHOLINE ACETYLTRANSFERASE
- Following synaptic release Ach degraded by ACETYLCHOLINESTERASE
Nicotinic receptors
- Channel opens to allow … in (and … out)
- Some subtypes allow … influx
Nicotinic receptors
- Channel opens to allow Na+ in (and K+ out)
- Some subtypes allow Ca2+ influx
Muscarinic receptors
…. …. receptor
Muscarinic receptors
GPROTEIN COUPLED receptor
GABA
- An … … neurotransmitter
- But … found in proteins
- Synthesized only in … neurons by glutamic acid decarboxylase (…)
- GAD therefore a good marker for …. neurone
- Gaba neurons distributed widely in …
- Following release GABA taken up by terminals or … …
GABA
- An AMINO ACID neurotransmitter
- But NOT found in proteins
- Synthesized only in GABAnergic neurons by glutamic acid decarboxylase (GAD)
- GAD therefore a good marker for GABAnergic neurone
- Gaba neurons distributed widely in CNS
- Following release GABA taken up by terminals or GLIAL CELLS
GABA receptors
- GABA action generally …
- Involves both … (GABAa) and … (GABAb) receptors
- GAbAa receptors are GABA-gated … channels
- In some neurons Cl- may … and GABA is ….
GABA receptors
- GABA action generally INHIBITORY
- Involves both IONOTROPIC (GABAa) and METABOTROPIC (GABAb) receptors
- GAbAa receptors are GABA-gated Cl- channels
- In some neurons Cl- may EFFLUX and GABA is EXCITATORY
GABAa receptors
- …. increase opening frequency
- …. increases opening duration
- … also increases GABA action but depends on subunit structure of the receptor
- These exogenous agents may be mimicking endogenous modulators such as …
GABAa receptors
- BENSODIAZEPINES increase opening frequency
- BARBITURATES increases opening duration
- ETHANOL also increases GABA action but depends on subunit structure of the receptor
- These exogenous agents may be mimicking endogenous modulators such as NEUROSTEROIDS
GABAa receptors
- Drugs that enhance GABA action are …
- They reduce … (or panic)
- Individuals with anxiety disorders may have … GABA activity
GABAa receptors
- Drugs that enhance GABA action are ANXIOLYTIC
- They reduce ANXIETY (or panic)
- Individuals with anxiety disorders may have REDUCED GABA activity
Catecholamines
- Synthesised from …. by … …. (TH)
- Produces …
- In certain neurons synthesis continues to … & …
- TH activity reduced by …. ….
- TH activity increased by … influx resulting from enhanced stimulation
Catecholamines
- Synthesised from TYROSINE by TYROSINE HYDROXYLASE (TH)
- Produces L-DOPA
- In certain neurons synthesis continues to NORADRENALINE & ADRENALINE
- TH activity reduced by FEEDBACK INHIBITION
- TH activity increased by Ca2+ influx resulting from enhanced stimulation
Dopamine
Involved in …, …, attention and neuroendocrine
All mediated by … … receptors
Action terminated by reuptake by …. …. or …
Stimulants (cocaine and amphetamines) … reuptake, thus prolonging dopamine action
Dopamine
Involved in MOVEMENT, MOOD, attention and neuroendocrine
All mediated by G-PROTEIN COUPLED receptors
Action terminated by reuptake by NERVE TERMINAL or GLIA
Stimulants (cocaine and amphetamines) INHIBIT reuptake, thus prolonging dopamine action
Dopamine
Dopaminergic neurons throughout ….
Facilitates initiation of …
Death of SN cells results in …. disease
Treat with ….
Dopamine
Dopaminergic neurons throughout CNS
Facilitates initiation of MOVEMENT
Death of SN cells results in PARKINSONS disease
Treat with L-DOPA
Dopamine
- L-dopa crosses into ..
- Converted into …
- But only in … neurons
- Doesnt stop ….
Dopamine
- L-dopa crosses into BRAIN
- Converted into DOPAMINE
- But only in SURVIVING neurons
- Doesnt stop DEGENERATION
VTA dopamine system also known as the …. system
- A reward system which reinforces desirable …
- … & … stimulate VTA dopamine neurones
- … & …. increases DA at the synapse
- … stimulation of reward pathway
VTA dopamine system also known as the MESOCORTICOLIMBIC system
- A reward system which reinforces desirable BEHAVIOURS
- OPIATES & NICOTINE stimulate VTA dopamine neurones
- COCAINE & AMPHETAMINES increases DA at the synapse
- INCREASES stimulation of reward pathway
Prolonged activation of VTA results in ….
- Generates … tolerance
- Amphetamine addiction shows features of ….
Prolonged activation of VTA results in DOWN-REGULATION
- Generates DRUG tolerance
- Amphetamine addiction shows features of SCHIZOPHRENIA
Dopamine and schizophrenia
Drugs effective against the “positive” symptoms of schizophrenia are called … or ….
Atypical antipsychotics block … … receptors
Dopamine and schizophrenia
Drugs effective against the “positive” symptoms of schizophrenia are called NEUROLEPTICS or ANTIPSYCHOTICS
Atypical antipsychotics block DOPAMINE D2 receptor
ATP
- Acts on … …
- both … … and … …
ATP
- Acts on PURINERGIC RECEPTORS
- both ION CHANNELS and G-PROTEIN COUPLED
Endocannabinoids
- …. ligand for the cannabis receptor(s)
- Synthesized in the ….. terminals in response to Ca2+ inflow
- Acts as a … … to the presynaptic terminal
- Activates … receptors which are coupled to G-proteins
Endocannabinoids
- ENDOGENOUS ligand for the cannabis receptor(s)
- Synthesized in the POST-SYNAPTIC terminals in response to Ca2+ inflow
- Acts as a RETROGRADE SIGNAL to the presynaptic terminal
- Activates CB1 receptors which are coupled to G-proteins
Hypothalamus composed of 3 zones
…., ….. & …..
Hypothalamus composed of 3 zones
LATERAL, MEDIAL & PERIVENTRICULAR
Periventricular has multiple functions including regulation of the …
Periventricular has multiple functions including regulation of the PITUITARY
….. neurons project to posterior lobe of pituitary
Release … & ….
MAGNOCELLULAR neurons project to posterior lobe of pituitary
Release OXYTOCIN & ADH
ADH regulates .. … …
Hypothalamus integrates multiple inputs relating to … … & …
ADH acts on … to increase … ….
ADH … blood vessels
ADH regulates EXTRACELLULAR FLUID VOLUME
Hypothalamus integrates multiple inputs relating to BLOOD PRESSURE & OSMOLALITY
ADH acts on KIDNEY to increase WATER RETENTION
ADH CONSTRICTS blood vessels
Oxytocin involved in …. contraction and … …
Oxytocin involved in UTERINE contraction and MILK EJECTION
The hypothalamus also controls the …. ….
- ….. neurons
The hypothalamus also controls the ANTERIOR PITUITARY
- PARVOCELLULAR neurons
Parvocellular neurons secrete ….. hormones into the hypothalamic pituitary … ….
- These signals travel to the .. ….
Parvocellular neurons secrete HYPOPHYSIOTROPIC hormones into the hypothalamic pituitary PORTAL CIRCULATION
- These signals travel to the ANTERIOR PITUITARY
Anterior pituitary releases
- - - - - -
Anterior pituitary releases
- Follicle stimulating hormone (FSH)
- Luteinizing hormone (LH)
- Thyroid stimulation hormone (TSH)
- Adrenocorticotropic hormone (ACTH)
- Growth hormone (GH)
- Prolactin
Steps of TRH:
- L23, page 18
Steps of TRH:
Steps of Prolactin
- L23, page 21
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Steps of CRH
- L23, page 26
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Steps of GnRH
- L23, page 30
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Estrogens are … and can enter the …
Estrogen receptors are widely distributed in the …
Concentrated in the .. & ….
Estrogens are LIPOPHILIC and can enter the BRAIN
Estrogen receptors are widely distributed in the CNS
Concentrated in the PITUITARY & HYPOTHALAMUS
What do CNS estrogen receptors do?
Feedback signals to ….
Influence … & … activity
Initiate and support … …. brain structures
What do CNS estrogen receptors do?
Feedback signals to HYPOTHALAMUS
Influence SEXUAL & REPRODUCTIVE activity
Initiate and support SEXUAL DIMORPHIC brain structures
What do CNS estrogen receptors do?
- Increase the number of … …
What do CNS estrogen receptors do?
- Increase the number of DENDRITIC SPINES
Estrogens may influence neuronal activity via:
- Classical … receptors to alter .. …
- And … receptors to have …., … effects
- These non-classical receptors may be located at or near the …
Estrogens may influence neuronal activity via:
- Classical INTRACELLULAR receptors to alter GENE TRANSCRIPTION
- And MEMBRANE receptors to have RAPID, NON-GENOMIC effects
- These non-classical receptors may be located at or near the SYNAPSE
Modulation of neurotransmission may provide a mechanism for …
referred to as … ….
Alterations must be … for the period of the memory
Modulation of neurotransmission may provide a mechanism for MEMORY
referred to as SYNAPTIC PLASTICITY
Alterations must be STABLE for the period of the memory
Advantages in using simple organisms (invertebrates)
- Small … …
- Neurons themselves are …
- Easy to identify … … and circuits
- Small … & rapid … …
Advantages in using simple organisms (invertebrates)
- Small NERVOUS SYSTEM
- Neurons themselves are LARGE
- Easy to identify INDIVIDUAL NEURONS and circuits
- Small GENOME & rapid LIFE CYCLE
- Aplysia demonstrates a level of … & ….
- Tactile stimulus to siphon causes .. …
- Touch activates .. … in the siphon skin
- Relayed to …. neuron (L7) in …. ganglion
- Stimulates .. … and thus gill withdrawal
- Aplysia demonstrates a level of LEARNING & MEMORY
- Tactile stimulus to siphon causes GILL WITHDRAWAL
- Touch activates SENSORY NEURONS in the siphon skin
- Relayed to MOTOR neuron (L7) in ABDOMINAL ganglion
- Stimulates GILL MUSCLES and thus gill withdrawal
- Repeated stimulus results in ….
- represents … ….
- Decreased ….. release from … neuron
- Fewer …. released per action potential
- Repeated stimulus results in HABITUATION
- represents WEAKENED NEUROTRANSMITTER
- Decreased NEUROTRANSMITTER release from SENSORY neuron
- Fewer VESICLES released per action potential
Aplysia can also demonstrate ….
- Threatening stimuli result in …. sensitivity of the gill-withdrawal response
- …. stimuli activate interneuron L29
- This … neurotransmitter release from the … neuron presynaptic terminal
Aplysia can also demonstrate SENSITIZATION
- Threatening stimuli result in INCREASED sensitivity of the gill-withdrawal response
- NOXIOUS stimuli activate interneuron L29
- This ENHANCES neurotransmitter release from the SENSORY neuron presynaptic terminal
L29 releases …
- Activates … receptors on presynaptic nerve terminal
- Stimulates formation of …
- Activates … … .. (PKA)
L29 releases 5HT
- Activates 5HT receptors on presynaptic nerve terminal
- Stimulates formation of cAMP
- Activates PROTEIN KINASE A (PKA)
- PKA increases … on specific proteins
- Phosphorylated K+ channels …
- … does not exit terminal as rapidly
- Voltage-sensitive … channels remain open
- Greater Ca2+ influx … release of neurotransmitter
- Stronger signal to .. …
- Enhances … …
- PKA increases PHOSPHORYLATION on specific proteins
- Phosphorylated K+ channels CLOSE
- K+ does not exit terminal as rapidly
- Voltage-sensitive Ca2+ channels remain open
- Greater Ca2+ influx INCREASES release of neurotransmitter
- Stronger signal to MOTOR NEURON
- Enhances GILL WITHDRAWAL
- Hippocampal input arrives from … …
- Synapse onto neurons in the .. …
- Axons from these neurons (mossy fibres) synapse onto … …
- Axons from CA3 neurons …:
- Out of hippocampus via …
- And Schaffer collaterals to synapse onto …. neurons
- Hippocampal input arrives from ENTORHINAL CORTEX
- Synapse onto neurons in the DENTATE GYRUS
- Axons from these neurons (mossy fibres) synapse onto CA3 CELLS
- Axons from CA3 neurons BRANCH
- Out of hippocampus via FORNIX
- And Schaffer collaterals to synapse onto CA1 neurons
What is the molecular mechanism responsible for LTP
The Schaffer collaterals release … on the … dendritic spines
AMPA channels open to allow … influx
NMDA channels open to allow … and … influx
But NMDA normally blocked by …
What is the molecular mechanism responsible for LTP
The Schaffer collaterals release GLUTAMATE on the CA1 dendritic spines
AMPA channels open to allow Na+ influx
NMDA channels open to allow Na+ and Ca2+ influx
But NMDA normally blocked by Mg2+
At … levels of activity glutamate released
Activates … receptor
… influx promotes small … of dendritic spine
NMDA channels remain …
At LOW levels of activity glutamate released
Activates AMPA receptor
Na+ influx promotes small DEPOLARIZATION of dendritic spine
NMDA channels remain CLOSED
At … levels of activity (tetanus) lots of glutamate released
Strong activation of … receptors
Large … influx promotes greater …. of dendritic spine
NMDA channels become ….
… and … enter dendritic spine
Calcium influx provides signal for … induction
At HIGH levels of activity (tetanus) lots of glutamate released
Strong activation of AMPA receptors
Large Na+ influx promotes greater DEPOLARIZATION of dendritic spine
NMDA channels become UNBLOCKED
Na+ and Ca+ enter dendritic spine
Calcium influx provides signal for LTP induction
Presynaptic facilitation in aplysia is mediated by … … of K+ channels
A form of PKA can be generated that is active w/out …
Will therefore continue to phosphorylate the … channels after cAMP levels have declined
Presynaptic facilitation in aplysia is mediated by PKA PHOSPHORYLATION of K+ channels
A form of PKA can be generated that is active w/out cAMP
Will therefore continue to phosphorylate the K+ channels after cAMP levels have declined
In LTP Ca2+ activates …
CaMKII phosphorylates …. receptors
CaMKI can also phosphorylate … (autophosphorylate)
Phosphorylated CaMKII is active w/out …
Thus continues to phosphorylate … receptors
In LTP Ca2+ activates CaMKII
CaMKII phosphorylates AMPA receptors
CaMKI can also phosphorylate ITSELF (autophosphorylate)
Phosphorylated CaMKII is active w/out CALCIUM
Thus continues to phosphorylate AMPA receptors
