Topic 13: Neuropeptides Flashcards
(33 cards)
What are neuropeptides?
similar in design and function to many peptide hormones of pituitary or gastrointestinal systems
many pituitary and GI hormones are neuroactive and used at selective sites in the CNS
far more neuropeptides than classical neurotransmitters
over 100 identified neuroactive peptides currently identified
at least 10 families, over 90 genes, many responsible for expression of multiple neuropeptides
How are neuropeptides formed?
neuroactive peptides derive from proteins
peptides formed from cleavage of polypeptides
inactive proteins that function exclusively as precursors to peptides
specific polypeptide precursors are termed propeptides or pre-propeptides
contain 2 or more amino acid linked by a peptide bond
smaller than proteins
What are the structures of peptides?
like proteins, peptides and pre-propeptides have a specific sequence of amino acids (N- and C- terminus)
peptides with similar structure often have very different functions
phylogenetically old: jellyfish, hydras, and corals often use peptides rather than classical neurotransmitters
How are peptides synthesized?
peptides are synthesized as polypeptide precursors, generally at least 90 amino acids
same general process as precursor proteins biosynthesis
occurs only in cell body
metabolism to active peptide is tissue specific: most precursor are expressed in more than one tissue and the processing is yields tissue specific peptide
How are pre-propeptides processed and transported?
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
How are propeptides cleaved into active peptides?
pro-opiomelanocrtin (POMC) gene produces a propeptide for:
alpha-, beta-, and gamma-melanocyte stimulating hormones (MSH)
adrenocorticotropic hormone (ACTH)
beta-endorphins
beta- and gamma-lipoproteins (LPH)
corticotropin-like intermediate peptide (CLIP)
Where does propeptide cleavage occur?
propeptide cleavage to active peptides occurs inside trafficking vesicles by synthesizing peptidases
What are signal peptidases?
endoplasmic reticulum
cleave signal sequence from pre-propeptide to generate propeptide
What are synthesizing peptidases?
LDCV
cleave propeptides to generate neuroactive peptides
What are catabolic peptidases?
extracellular
cleave active peptides to inactivate signalling
What are exopeptidases?
cleave single amino acid residues from either end of a peptide
catabolic pepetidases
What are endopeptidases?
cleave peptides within the sequence of the peptide
signaling and synthesizing peptidases are typically endopeptidases
What are the characteristics of neurotransmitters?
synthesized in the nerve terminal: synthetic machinery transported to nerve terminal from soma
released from small synaptic vesicles by exocytosis: closely coupled to calcium channels, relatively low calcium-sensitivity, calcium 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
What are the characteristics of neuropeptides?
synthesized only in the cell body: propeptides transported to nerve terminal from soma
released from LDCV by exocytosis: distant from sites of calcium-entry, highly sesnitive to calcium, calcium from internal or external sources
degraded after release, never recycled
low concentrations at nerve terminal: receptors respond to relatively low concentrations of neuropeptides
release can be extrasynaptic
How do neuropeptides function as modulators?
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
What sites do neuropeptides act on?
direct action on postsynaptic cell
presynaptic sites on the releasing cell (autocrine function)
on adjacent cells (juxtracrine functions)
on close cells (paracrine effects)
at distant sites requiring transport through circulatory system (endocrine effects)
What are neuroactive peptides?
tachykinin peptides: Substance P, neurokinins, neuromedins, neuropeptides K and gamma
cholecystokinin peptides: CCL & Gastrins
cocaine and amphetamine regulated trancript (CART)
orexigenic peptides: neuropeptide Y, ghrelin, orexin
oxytocin/vasopressin
What are tachykinin peptides (substance P)?
one of the earliest neuroactive peptides identified
Tachykinin family has at least 7 peptides
What are tachykinin genes?
two pre-protachykinin genes express all known tachykinin peptides
TAC1: substance P, neurokinin A, neuropeptide K, neuropeptide Y
TAC3: neuromedin K, neurokiin B
What are the three mammalian tachykinin receptors?
NK1, NK2, NK3
all are GPCR that signal through Gq
PLC –> IP3 and DAG –> Ca2+ release and PKC activation
How is substance P involved in nociception?
substance P is involved in pain transmission at the level of the spinal cord - involved in pain sensitization
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
What is capsaicin?
active component of chili peppers
produces intense burning sensation on contact with tissues
analgesic effect in topical application, depletes substance P
How is substance P involved in the vomit centre?
the chemoreceptor trigger zone (CTZ) of the area postrema (medulla) senses toxins in the bloodstream: BB 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
How are tachykinins involved 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
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)
