Neuropeptides Flashcards
What are neuropeptides similar to?
many peptide hormones of
pituitary or gastrointestinal systems
in terms of design and function
What are neuropeptides similar to?
Many pituitary and GI hormones
Where are neuropeptides’ sites of action?
selective sites in the CNS
How are neuropeptides compared to NTs?
NP > classical NTs
Describe general neuropeptide characteristics
- Over 100 identified neuroactive peptides currently identified
- At least 10 families, over 90 genes, many responsible for
expression of multiple neuropeptides
Describe peptide formation
formed from cleavage of
polypeptides
What are the function of inactive peptides?
Inactive proteins that function
exclusively as precursors to peptides
What are the common names for precursors?
propeptides or pre-propeptides
Describe characteristics of precursors
- Contain 2 or more amino acids linked by a peptide bond
- Smaller than proteins
What are the shared characteristic between proteins, peptides and pre-propeptides?
have a specific sequence of amino acids
What are the terminal names?
- N- and C-terminus
How are peptides synthesized?
- Peptides are synthesized as polypeptide
precursors - Same general process as protein biosynthesis
Where does synthesis occur?
only in cell body
describe peptide metabolism
- Metabolism to active peptide is tissue specific
Describe pre-propeptide processing and transport
- Pre-propeptides typically contain a series of hydrophobic amino acids at the N-terminus
- Signal sequence targets the transcribed polypeptide to the endoplasmic reticulum
- In the ER the signal sequence is cleaved by a signal peptidase
- Cleavage of the signal sequence produces an inactive propeptide
- Propeptides are packaged into large dense- core vesicles (LDCV) for transport to the nerve terminal
Describe prepropeptide cleavage to active peptide
- Pro-opiomelanocortin (POMC) gene
produces a propeptide for: - α-
, β-, and γ-melanocyte stimulating
hormones (MSH) - adrenocorticotropic hormone (ACTH)
- β-endorphins
- β- and γ-lipoproteins (LPH)
- Corticotropin-like intermediate peptide
(CLIP) - Propeptide cleavage to
active peptides occurs
inside trafficking vesicles by
synthesizing peptidases.
Describe signal peptidases
- Signal peptidases (ER)
- Cleave signal sequence from pre-propeptide to generate
propeptide
Describe neurotransmitters
- Synthesized in the nerve terminal
- Synthetic machinery transported to nerve terminal from
soma - Released from small synaptic vesicles by exocytosis
- Closely coupled to Ca2+
-channels - Relatively low Ca2+
-sensitivity - Ca2+ from external sources
- Recycled at the nerve terminal
- High concentrations at nerve terminal
- Receptors respond to relatively high concentrations of
NT - Release occurs at synapse
Describe neuropeptides
- Synthesized only in the cell body
- Propeptides transported to nerve terminal from soma
- Released from LDCV by exocytosis
- Distant from sites of Ca2+
-entry - Highly sensitive to Ca2+
- Ca2+ from internal or external sources
- Degraded after release
- Low concentrations at nerve terminal
- Receptors respond to relatively low concentrations of
neuropeptides - Release can be extrasynaptic
Why do neuropeptides do this?
- Neuropeptides are proposed to function as modulators of classic
neurotransmitter systems - Neuropeptide release can strengthen or prolong actions of primary
neurotransmitters - Correspondingly, most neuropeptide receptors are G-protein coupled
receptors - There are more receptors than peptides (subtypes exist for most
neuropeptides) - Receptors are often found at sites distal to synapses
Describe neuropeptide functions
- Neuropeptides may act at many sites
- Direct action on postsynaptic cell
- Presynaptic sites on the releasing cell (autocrine function)
- On adjacent cells (juxtacrine functions)
- On close cells (paracrine effects)
- At distant sites requiring transport through circulatory
system (endocrine effects)
Describe neuroactive peptides
- Tachykinin peptides
- Substance P
- Cholecystokinin peptides
- CCK & Gastrins
- Cocaine- and amphetamine regulated transcript (CART)
- Orexigenic peptides
- Neuropeptide Y, ghrelin, orexin
- Oxytocin / vasopressin
Describe Substance P
- One of the earliest neuroactive peptides
identified - 1931 Ulf von Euler and John Gaddum
identified a tissue extract that caused
intestinal contraction in an ex vivo
preparation - Named Substance P
- 1970 Nobel Prize for von Euler
- Identified as an 11-amino acid peptide in 1971
- Tachykinin family has at least 7 peptides
Describe tachykinin genes
- Two pre-protachykinin genes express
all known tachykinin peptides - TAC1
- Substance P
- All are GPCR that signal through
Gq - PLC → IP3 and DAG → Ca2+
release and PKC activation
Describe nociception
Substance P is
involved in pain
transmission at the
level of the spinal cord
– involved in pain
sensitization.
Describe the link between Substance P and pain
- Substance P is used in nociception
- Substance P is co-released from glutamatergic sensory afferents
- Transmission of information from damaged tissues to peripheral nerves
- Regulates sensitization of pain fibers (C fibers)
- Proposed to be involved in fibromyalgia and neuropathic pain
- NK2 and NK3 agonists reduce the response threshold for noxious stimuli
- Antagonists for NK1 and NK2 are being explored as possible targets for
analgesic drugs
Describe capsaicin
- Active component of chili
peppers - Produces intense burning
sensation on contact with
tissues - Analgesic effect in topical
application - Depletes Substance P
Describe Substance P in the vomit centre
- The chemoreceptor trigger zone (CTZ)
of the area postrema (medulla)
senses toxins in the bloodstream - BBB permeable area
- Also detects excess 5HT from the gut via
5HT3 channels - The tachykinin receptor NK1 is
expressed in late, convergent steps of
the vomit pathway - Substance P release in the CTZ is a
final triggering step of the vomit reflex - Apripitant is an NK1 substance P
antagonist used as an anti-emetic for
chemotherapy and post-operative
nausea
Describe role of tachykinins in psych. disease
- Pharmaceuticals affecting the tachykinin receptors are being explored in
psychiatric diseases and suggest a role for tachykinins in depression,
Schizophrenia, anxiety, and addictions - NK1 antagonists have antidepressant effects in animal models
- NK1 knockout mice show decreased voluntary alcohol consumption and NK1
antagonists decreased alcohol cravings in preclinical trials of detoxified
alcoholic inpatients - NK2 antagonists have anxiolytic and antidepressant effects in animal models
- NK3 antagonists have antipsychotic effects in clinical trials (with very limited
side effects)
Describe CCK peptides
- Cholecystokinin (CCK) family includes CCK
and gastrins - Derived from two pre-proCCK, pre-proGastrin
genes - Gastrointestinal peptide hormones that
normally triggers digestion of fat and protein - Triggers release of digestive enzymes and bile
from the pancreas and gallbladder,
respectively - Acts as a hunger suppressant in response to
presence of fat/protein rich foods
Describe CCK expression
widely expressed in the CNS
Describe effects of CCK administration
nausea and emesis,
satiety
Describe the proposed method of CCK function
act through the vagus nerve as circulating peptides are generally
unable to cross the BBB
Describe the role of CCK in abnormal behaviour
CCKR polymorphisms are associated with panic disorder and
schizophrenia
Describe CCK antagonist similarity with benzos
- CCK receptor antagonists share structure and affinity with
benzodiazepine
Describe effects of benzodiazepine treatment on CCK
- Chronic benzodiazepine treatment decreases neural
responsiveness to CCK
Describe effects of benzodiazepines withdrawal
- CCK receptor density is upregulated
Describe brain regions impacted
Esp. hippocampus and frontal cortex
Describe CCK receptor antagonists
- CCK receptor antagonists produce anxiolytic effects in animal
models
Describe proglumide
- Proglumide is a CCKA and CCKB antagonist used to treat stomach
ulcers
Describe effects in animal models
- Anxiolytic in animal models
Describe effects of opioids and role in tolerance
- Increases the analgesic effect of opioids and decreases the development of
opioid analgesic tolerance in humans - Prevents the development of analgesic tolerance to other pain treatments
e.g. transcutaneous electrical nerve stimulation (animal models)
What is the nocebo effect?
opposite phenomenon to the placebo effect
Expectation of symptom worsening leads to negative outcome
What were the results of nocebo research?
Research models of the nocebo in healthy volunteers uses verbally induced nocebo hyperalgesia
(increased sensitivity to pain on expectancy)
Describe the link between HPA axis and pain
Decreased pain threshold is associated with increased activation of the HPA axis (stress response leading to
cortisol release)
Describe the role of diazepam
reduces both hyperalgesia and HPA axis activity suggesting anxiety
contributes to the nocebo effect
Describe the role of proglumide
blocked the hyperalgesia of verbally induced nocebo but
not the HPA axis activity
Describe CCK and anxiety
Suggests CCK affects nocebo independent or downstream of anxiety
What does CART stand for?
Cocaine- and amphetamine-regulated
transcript
What type of peptide is CART?
Endogenous psychostimulant and anorexic peptide
Describe upregulatory agents of CART
cocaine or amphetamine (?*)
Describe the proposed functions of CART
some central effects of psychostimulants
What are CART’s effects when admin. alone?
induces locomotor hyperactivity
What are CART’s effects when admin. with cocaine?
inhibits motor hyperactivity
Where is CART expressed?
- Highly expressed in the hypothalamus
Describe modifiers of expression
modified by alcohol, nicotine, opioids
Describe the role of CART in addiction
prevents reinstatement of abuse (animal models)
Describe CART’s role in hunger suppression
Inhibits known orexigenic pathways
- CART signals downstream of 5HT in supressing appetite in the
hypothalamus
What are the effects of CARt deficit
- Deficits in CART expression have been associated with binge eating
(animal models) - Treatments for binge-eating (rimonabant) increase CART expression
What do synthesizing peptidases do?
- Synthesizing peptidases (LDCV)
- Cleave propeptides to generate neuroactive peptides
What do catabolic peptidases do?
- Catabolic peptidases (extracellular)
- Cleave active peptides to inactivate signalling
Describe exopeptidases
Exopeptidases cleave single amino acid residues from either end of a peptide (catabolic)
Describe endopeptidases
Endopeptidases cleave peptides within the sequence of the peptide (2 s peptidases)
