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protein embedded in membrane mechanism for neurotransmitter to influence postsynaptic activity by binding to receptor – PowerPoint PPT presentation

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Title: protein%20embedded%20in%20membrane


1
postsynaptic receptors
  • protein embedded in membrane
  • mechanism for neurotransmitter to influence
    postsynaptic activity by binding to receptor

2
Neurotransmitters and Receptors
  • There are different varieties of receptors.
  • Some respond fast
  • Called Ionotropic
  • Direct reaction to the transmitter

3
Neurotransmitters and Receptors
  • Different varieties of receptors
  • Other types of receptors respond more slowly.
  • Indirectly
  • Called Metabotropic, or G protein-coupled
  • Initiates a second signal (messenger) inside the
    neuron.

4
Neurotransmitters and Receptors
  • Inactivation Termination of Synaptic
    Transmission
  • Metabolism
  • Re-uptake

5
E
6
Neurotransmitters and Receptors
  • Acetylcholinefirst to be recognized, because of
    peripheral actions
  • Synthesis
  • Acetyl-CoA (in mitochondria) choline (from diet)

7
Acetylcholine
Choline Acetyl cOA
cHat (choline acetyl transferase)
Acetylcholine (ACh)
Choline acetate
AChE (Acetylcholinesterase)
8
Neurotransmitters and Receptors
  • Inactivation
  • Acetylcholinesterase (AChE)
  • After action in postsynaptic cleft, AChE degrades
    ACh to choline and acetate, which are taken back
    up into the neuron.

9
ACh
  • found in both CNS (brain and SC) and PNS (Somatic
    and autonomic NS)

10
Acetylcholine (ACh)
  • Functions (in CNS)
  • memory, sensory processing, movement, REM sleep
  • Functions (in PNS)
  • many psychotropics have anti ACh effects

11
Acetylcholine (ACh)
  • cholinergic receptor subtypes
  • 2 classes
  • labeled by agents that act as agonists at
    receptor

12
Acetylcholine (ACh)
  • nicotinic muscle, neuronal - majority are
    ionotropic
  • at least 17 subtypes
  • some muscular some CNS
  • number of nicotinic receptors are growing..

13
Nicotinic drugs..
  • nicotinic agonists
  • varenicline (Chantix) smoking cessation
  • partial agonist
  • nicotinic antagonist
  • botox- botulism toxin

14
Acetylcholine (ACh)
  • muscarinic
  • 5 subtypes discovered so far all metabotropic
  • (M1-M5)

15
Some Pharmacological Actions for M ACh
antagonists
  • scopolamine motion sickness
  • some meds for asthma
  • treating side effects of some PD meds

16
Acetylcholine (ACh)
  • ways to alter ACh activity
  • AChE inhibitors
  • some irreversible AChE inhibitors
  • malathion, parathion, (pesticides)
  • nerve gas (Sarin)
  • reversible
  • cognitive enhancers
  • donepezil (Aricept)

17
Disease states that involve ACh neurons
  • MG myasthenia gravis
  • autoimmune disease affecting NMJ
  • Alzheimers Disease - AD
  • temporary fixes for these disease states
  • reversible AChE inhibitors -tacrine (Cognex),
    donepezil (Aricept)
  • Strategy in both cases

18
Anticholinergic Side Effects
  • can include confusion, blurred vision,
    constipation, dry mouth, light-headedness,
    urinary retention, loss of bladder control.

19
choline rich foods Whole eggs, liver, beef
steak, and soy are among foods naturally rich in
choline.
20
catecholamines
  • Dopamine (DA)
  • Norephinephrine (NE)

21
catecholamines
  • NE and E are synthesized from their precursor DA
    with the appropriate enzymes present

22
tyrosine hydroxylase
DA decarboxylase
DA ß hydroxylase
PNMT
23
How are catecholamines taken removed from the
synapse?
  • Catecholamines removed by reuptake
  • DAT DA transporter
  • NET NE transporter

24
Neurotransmitters and Receptors
  • Catecholamines
  • Synthesis
  • Tyrosine
  • Dopamine
  • Norepinephrine
  • Termination
  • Re-uptake
  • Monoamine oxidase (MAO)

25
metabolism
  • metabolism
  • far slower than ACh by AChE
  • MAO enzymes (monoamine oxidase)
  • MAOA AND MAOB enzymes
  • MAO A more selective for NE and 5HT
  • MAO B- more selective for DA

26
  • Major metabolites
  • Important when trying to study potential
    differences
  • DA - dopac and HVA
  • NE - MHPG -(3-methoxy-4-hydroxy-phenethyleneglyco
    l)

27
Tyrosine
catecholamines
Tyrosine hydroxylase (rate limiting step) TH
DOPA
Aromatic acid decarboxylase
mao
homovanillic acid (HVA)
Dopamine (DA)
DA-ß-hydroxylase
MHPG
mao
pnmt
Epinephrine (E)
Norepinephrine (NE)
28
DA (dopamine)
  • CNS - reward, movement, motivated behaviors,
    executive function?
  • numerous DA pathways in CNS of importance for
    psychotropics..

29
DA receptor subtypes
  • DA receptor subtypes
  • 2 major families D1 and D2 families

30
NE (norepinephrine)
  • In CNS- arousal role in depression, possible
    role in spinal analgesia, possible motivated
    behaviors such as hunger, thirst, sex, anxiety,
    drug reward?
  • NE is in both the CNS and PNS

31
NE receptor subtypes
  • receptor subtypes
  • alpha 1 and 2 ß 1 3

32
5HT
  • more recent in our history of studying NT
  • similarity to LSD
  • found early in high concentrations in the gut
  • found in many non neuronal cells (only 1 2
    of 5HT in whole body is in brain)
  • cannot cross bbb so

33
5HT
  • synthesis
  • amino acid precursor tryptophan
  • elimination of dietary tryptophan can
    significantly lower brain 5HT levels
  • foods high in tryptophan
  • nuts (ie walnuts, almonds), tofu, milk, eggs,
    certain cheeses, turkey, seafood, seeds

34
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35
5HT
  • behavioral role (CNS) sleep, aggressive behavior
  • abnormal function implicated in
  • schizophrenia, depression, phobic disorders, OCD,
    eating disorders, migraine, etc

36
5HT
  • receptor subtypes-
  • many at least 18 subtypes have been identified
  • - probably best way to group 5HT1 and 5HT2
    families
  • - some are metabotropic some ionotropic

37
5HT
  • reuptake main mechanism for terminating
  • SSRIs
  • breakdown major metabolite 5HIAA

38
amino acid neurotransmitters
  • pervasive throughout the brain
  • classified into 2 general categories
  • excitatory (glutamate, aspartate)
  • inhibitory (GABA, glycine)
  • amino acids are more difficult to classify as nt

39
GABA
  • first identified in leg of lobster
  • causes hyperpolarization of neurons
  • highest concentrations in brain and spinal cord
    and virtually absent in peripheral nerve or other
    organs
  • does not cross bbb easily

40
GABA
  • stored in synaptic vesicles (like other nt)
  • usually removed from synapse via transporter
    (GAT)
  • GABA also found in glia
  • receptor subtypes
  • GABA A ionotropic clinically important
  • GABA B - metabotropic

41
GABA A
  • mediates anxiolytic, sedative, anticonvulsant,
    muscle-relaxant and amnesic activity
  • subunit compositions appear to vary from one
    brain region to another and even between neurons
    within a given region
  • anticonvulsants are being considered for various
    psychiatric disorders

42
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43
modulatory effects
44
glutamate
  • found in high concentrations in brain
  • serves many functions
  • receptor subtypes
  • tremendous work done in recent years

45
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46
glutamate
  • receptor subtypes
  • NMDA, ionotropic, various other receptors
    including metabotropic GLU R (mGLUR)
  • families within these
  • role of neuromodulators
  • current potential interests
  • reducing neurotoxicity, psychiatric disorders,
    substance use disorders, Alzhemiers Disease?

47
Neurotransmitters and Receptors
  • Peptides
  • Opioids
  • Mu
  • Delta
  • Kappa
  • Endorphins and enkephalins are opioids
  • Substance P
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