Neuropeptides Flashcards
1
Q
Neuropeptides
A
Similar in design and function to many peptide hormones of
pituitary or gastrointestinal systems
2
Q
Many pituitary and GI hormones are
A
neuroactive and used at
selective sites in the CNS
3
Q
Far more neuropeptides than
A
classical neurotransmitters
4
Q
Far more neuropeptides than classical neurotransmitters Over
A
100 identified neuroactive peptides currently identified
5
Q
Far more neuropeptides than classical neurotransmitters how many families and how many genes
A
At least 10 families, over 90 genes, many responsible for
expression of multiple neuropeptides
6
Q
Neuroactive peptides derive from
A
proteins
7
Q
Peptides formed from
A
cleavage of
polypeptides
8
Q
Specific polypeptide precursors are
termed
A
propeptides or pre-propeptides
9
Q
Peptides formed from cleavage of
polypeptides inactive proteins that function
exclusively as
A
precursors to peptides
10
Q
Neuroactive peptides derive from proteins Contain 2 or more
A
amino acids linked
by a peptide bond
11
Q
Neuroactive peptides derive from proteins Smaller than
A
proteins
12
Q
Peptide structures * Like proteins, peptides and pre-propeptides
have a
A
specific sequence of amino acids
13
Q
Like proteins, peptides and pre-propeptides
have a specific sequence of amino acids
A
- N- and C-terminus
14
Q
Peptides with similar structure often have very
A
different functions
15
Q
Jellyfish, hydras, and corals often use
A
e peptides
rather than classical neurotransmitters
16
Q
Peptides are
A
Phylogenetically old
17
Q
Peptides are synthesized as
A
s polypeptide
precursors, generally at least 90 amino acids
18
Q
Peptide synthesis Same general process as
A
protein biosynthesis
19
Q
Peptide synthesis Occurs only in
A
cell body
20
Q
Metabolism to active peptide is
A
tissue specific
21
Q
Metabolism to active peptide is tissue specific Most precursors are
A
expressed in more than
one tissue and the processing is yields tissue
specific peptide
22
Q
Pre-propeptides typically contain a series of
A
hydrophobic amino acids at the N-terminus
23
Q
Pre-propeptides typically contain a series of
hydrophobic amino acids at the N-terminus signaling
A
sequence targets the transcribed
polypeptide to the endoplasmic reticulum
24
Q
In the ER the signal sequence is
A
s cleaved by a
signal peptidase
25
* Cleavage of the signal sequence produces
an
inactive propeptide
26
Propeptides are packaged into
large densecore vesicles (LDCV) for transport to the
nerve terminal
27
Propeptide cleavage to active peptide Pro-opiomelanocortin (POMC) gene
produces a propeptide for
1. α-, β-, and γ- (MSH)
2. adrenocorticotropic hormone (ACTH)
3. β-endorphins
4. β- and γ-lipoproteins (LPH)
5. Corticotropin-like intermediate peptide
(CLIP)
28
Propeptide cleavage to
active peptides occurs
inside
trafficking vesicles by
synthesizing peptidases.
29
Signal peptidases (ER)
Cleave signal sequence from pre-propeptide to generate
propeptide
30
Synthesizing peptidases (LDCV)
Cleave propeptides to generate neuroactive peptides
31
Catabolic peptidases (extracellular)
* Cleave active peptides to inactivate signalling
32
Exopeptidases
cleave single amino acid residues from either end of a peptide
33
Endopeptidases
cleave peptides within the sequence of the peptide
34
Catabolic peptidases are typically
exopeptidases
Signalling
35
synthesizing peptidases are typically
endopeptidases
36
Neurotransmitter Synthesized in
n the nerve terminal
37
Neurotransmitter Synthetic machinery transported to
nerve terminal from
soma
38
Neurotransmitter Released from small
synaptic vesicles by exocytosis
39
Neurotransmitter Released from small synaptic vesicles by exocytosis Closely coupled to
Ca2+
-channels
40
Neurotransmitter Released from small synaptic vesicles by exocytosis Relatively low
Ca2+
-sensitivity
41
Neurotransmitter Released from small synaptic vesicles by exocytosis Ca2+ from
external sources
42
Neurotransmitter Recycled at the
nerve terminal
43
Neurotransmitter High concentrations at
nerve terminal
44
Neurotransmitter High concentrations at nerve terminal
Receptors respond to relatively high concentrations of
NT
45
Neurotransmitter * Release occurs at
synapse
46
Neuropeptide Synthesized only in the
cell body
47
Neuropeptide Synthesized only in the cell body
Propeptides transported to nerve terminal from soma
48
Neuropeptide Released from
LDCV by exocytosis
49
Neuropeptide Released from LDCV by exocytosis Distant from sites of
Ca2+
-entry
50
Neuropeptide Released from LDCV by exocytosis Highly sensitive to
Ca2+
51
Neuropeptide Released from LDCV by exocytosis Ca2+ from
internal or external sources
52
Neuropeptides Degraded after
release
53
Neuropeptide Low concentrations at
nerve terminal
54
Neuropeptide Low concentrations at nerve terminal
* Receptors respond to relatively low concentrations of
neuropeptides
55
Neuropeptide Release can be
extrasynaptic
56
* Neuropeptides are proposed to function as
modulators of classic
neurotransmitter systems
57
* Neuropeptide release can
strengthen or prolong actions of primary
neurotransmitters
58
Correspondingly, most neuropeptide receptors are
G-protein coupled
receptors
59
Neuropeptides are proposed to function as modulators of classic
neurotransmitter systems
There are more receptors than
peptides
60
Neuropeptide Receptors are often found at sites
distal to synapses
61
Neuropeptide functions Neuropeptides may act at many sites Direct action on
postsynaptic cell
62
Neuropeptide functions Neuropeptides may act at many sites Presynaptic sites on the
releasing cell (autocrine function)
63
Neuropeptide functions Neuropeptides may act at many sites * On adjacent cells
(juxtacrine functions)
64
Neuropeptide functions Neuropeptides may act at many sites On close cells
(paracrine effects)
65
Neuropeptide functions Neuropeptides may act at many sites At distant sites requiring transport through circulatory
system
(endocrine effects)
66
Neuroactive peptides Tachykinin peptides
Substance P, neurokinins, neuromedins, neuropeptides K & γ
67
Neuroactive peptides Cholecystokinin peptides
CCK & Gastrins
68
Neuroactive peptides Cocaine- and amphetamine regulated transcript
(CART)
69
Neuroactive peptides Orexigenic peptides
Neuropeptide Y, ghrelin, orexin
70
Neuroactive peptides Oxytocin / vasopressin
same
71
Tachykinin Peptides – Substance P
One of the earliest neuroactive peptides
identified intestinal contractions
72
Tachykinin Peptides – Substance P Identified as an
11-amino acid peptide
73
Tachykinin family has at least
7 peptides
74
Tachykinin genes Two pre-protachykinin genes express
all known tachykinin peptides
TAC1, TAC3
75
TAC1
Substance P, neurokinin A, neuropeptide
K, neuropeptide γ
76
* TAC3
Neuromedin K, neurokinin B
77
Three mammalian tachykinin
receptors
NK1
* NK2
* NK3
78
All are GPCR that signal through
Gq
79
All are GPCR that signal through
Gq
* PLC → IP3 and DAG → Ca2+
release and PKC activation
80
Nociception
Substance P is
involved in pain
transmission at the
level of the spinal cord – involved in pain
sensitization.
81
Substance P and pain
* Substance P is used in nociception
82
Substance P is co-released from
glutamatergic sensory afferents
83
Substance P is used in nociception Transmission of information from
damaged tissues to peripheral nerves
84
Substance P is used in nociception Regulates sensitization of
pain fibers (C fibers)
85
Substance P is used in nociception Proposed to be involved in
fibromyalgia and neuropathic pain
86
NK2 and NK3 agonists reduce the
response threshold for noxious stimuli
87
Antagonists for NK1 and NK2 are being explored as possible targets for
analgesic drugs
88
Capsaicin
Active component of chili
peppers Produces intense burning
sensation on contact with
tissues
89
Capsaicin Analgesic effect in
topical
application
90
Capsaicin Analgesic effect in topical
application
Depletes Substance P
91
Substance P in the vomit center
* The chemoreceptor trigger zone (CTZ)
of the area postrema (medulla)
senses toxins in the bloodstream
92
The chemoreceptor trigger zone (CTZ)
of the area postrema (medulla)
senses toxins in the bloodstream
BBB
BBB permeable area
93
The chemoreceptor trigger zone (CTZ)
of the area postrema (medulla)
senses toxins in the bloodstream Also detects excess
5HT from the gut via
5HT3 channels
94
The tachykinin receptor NK1 is
expressed in late,
convergent steps of
the vomit pathway
95
Substance P release in the CTZ is a
final triggering step of the vomit reflex
96
Apripitant is an
n NK1 substance P
antagonist used as an anti-emetic for
chemotherapy and post-operative
nausea
97
Tachykinins in psychiatric disease
* Pharmaceuticals affecting the tachykinin receptors are being explored in
psychiatric diseases and suggest a role for tachykinins in depression,
Schizophrenia, anxiety, and addictions
98
NK1 antagonists have
antidepressant effects in animal models
99
NK1 knockout mice show
decreased voluntary alcohol consumption
100
NK1
antagonists decreased
alcohol cravings in preclinical trials of detoxified
alcoholic inpatient
101
NK2 antagonists have
anxiolytic and antidepressant effects in animal models
102
NK3 antagonists have
antipsychotic effects in clinical trials (with very limited
side effects)
103
CCK Family peptides Cholecystokinin (CCK) family includes CCK
and gastrins Derived from two pre
pre
-proCCK, pre
-proGastrin
genes
104
CCK Family peptides Gastrointestinal peptide hormones that
normally triggers digestion of fat and protein
105
CCK Gastrointestinal peptide hormones that
normally triggers digestion of fat and protein
Triggers release of digestive enzymes and bile
from the pancreas and gallbladder,
respectively
106
CCK Family peptides Acts as a
a hunger suppressant in response to
presence of fat/protein rich foods
107
CCK Family in the CNS CCK peptides are a family designated based on the
length in amino acids
108
CCK Family in the CNS CCK peptides commonly found in the CNS
CCK4, CCK8, CCK22, CCK33, CCK58
109
CCK receptors are widely expressed in the
CNS
110
* Administration of CCK into systemic circulation triggers
nausea and emesis,
as well as satiety
111
Administration of CCK into systemic circulation triggers nausea and emesis,
as well as satiety Thought to act through the
vagus nerve as circulating peptides are generally
unable to cross the BBB
112
CCKR polymorphisms are associated with
panic disorder and
schizophrenia
113
CCK4 and anxiety CCK4 administration is used as a model of
anxiety
114
* IV administration of CCK4
induces anxiety and panic attacks
115
CCK4* Can be used to test
anxiolytic drugs in healthy volunteers
116
CCK4 Administration of peptides into systemic circulation elicits very
transient effects as the peptides are rapidly metabolised
117
CCK plays some role in
nociception
118
CCK may play an important role in
anxiety disorders
119
CCK and benzodiazepines
CCK receptor antagonists share structure and affinity with
benzodiazepines
120
Chronic benzodiazepine treatment decreases neural
responsiveness to
CCK
121
* CCK receptor density is upregulated during
g benzodiazepine
withdrawal
122
CCK receptor density is upregulated during benzodiazepine
withdrawal esp
hippocampus and frontal cortex
123
* CCK receptor antagonists produce
anxiolytic effects in animal
models
124
Proglumide
is a CCKA and CCKB antagonist used to treat stomach
ulcers
125
Anxiolytic in
CCK receptor antagonists
126
CCK receptor antagonists produce Increases the analgesic effect of
opioids and decreases the development of
opioid analgesic tolerance in humans
127
CCK receptor antagonists Prevents the development of
analgesic tolerance to other pain treatments
e.g. transcutaneous electrical nerve stimulation (animal models)
128
CCK and the ‘nocebo’ effect
CCK receptor antagonists (proglumide) blocked the hyperalgesia of verbally induced nocebo but
not the HPA axis activity
129
CCK receptor antagonists (proglumide) blocked the hyperalgesia of verbally induced nocebo but
not the HPA axis activity
Suggests CCK affects nocebo independent or downstream of anxiety
130
Diazepam treatment reduces both
hyperalgesia and HPA axis activity suggesting anxiety
contributes to the nocebo effect
131
Research models of the nocebo in healthy volunteers uses
verbally induced nocebo hyperalgesia
(increased sensitivity to pain on expectancy)
132
Research models of the nocebo in healthy volunteers uses verbally induced nocebo hyperalgesia
(increased sensitivity to pain on expectancy) Decreased pain threshold is associated with
increased activation of the HPA axis (stress response leading to
cortisol release)
133
Cocaine- and amphetamine-regulated
transcript (CART)
* Endogenous psychostimulant and anorexic peptide
134
(CART) Upregulated by
cocaine or amphetamine
135
(CART May be responsible for some
central effects of psychostimulants
136
* CART alone induces _____ but co-administration with
locomotor hyperactivity BUT co-administration with
cocaine inhibits motor hyperactivity
137
CART expression is modified by
alcohol, nicotine, opioids
138
CART administration prevents
reinstatement of abuse (animal models)
139
(CART) Highly expressed in the
hypothalamus
140
(CART) Inhibits known
orexigenic pathway
141
CART signals downstream of
5HT in supressing appetite in the
hypothalamus
142
Deficits in CART expression have been associated with
binge eating
143
* Treatments for binge-eating (rimonabant) increase
CART expression
