Neuropeptides Flashcards
Peptide Hormones vs. Neuropeptides
o Neuropeptides – act on nearby cells; vary in length from 3-36 amino acids
o Peptide hormones – act on distal cells/tissues
Major Differences in Synthesis of NT and Neuropeptides
o Neuropeptides synthesized from mRNA in neuron/glial cells; neurotransmitters are produced from AA and have rate limiting step enzymes
Fast Amino Acid Neurotransmitter Characteristics
– glutamate, GABA, glycine –
Stored in clear synaptic vessels and released BEFORE neuropeptides
Fast vesicle recycling
Ultra short distance
Ionotropic receptors
Low frequency stimulation causes release
Slow Neuropeptide Transmission
– hypocretin, NPY, MCH, POMC, vasopressin, dynorphin, substance P – modulate neural activity
Stored in large dense core vesicles and released AFTER AA NT release
Slow vesicle recycling
Local diffusion
Can bind to G-protein coupled receptors; or modulate other receptors
High frequency stimulation causes extra-synaptic release – not in synaptic cleft
Neuropeptide Transmitter Functions
- pain, appetite, cardio/respiratory, GI, reward, fear, locomotion, immune suppressors, mood, pleasure, pain, weight, and energy
Opioid Peptides
o Enkephalins – peptide neurotransmitter; reduces pain
4 conserved amino acid sequence; additional AA form different enkephalins
o Endorphins – endogenous morphine; reduces pain
Same 4 conserve AA sequence as enkephalins and therefore part of enkephalin family
Less strong bind with less affinity to opioid receptor and degrade faster
Beta-endorphins – released from brain during exercise and reduce the intensity of pain
o Dynorphin
Substance P and NAAG
- Substance P – modulates pain
* NAAG – smallest neuropeptide (2 amino acids)
Neuropeptide Processing
o Prohormone convertase 1 and 2 – endoproteolysis between basic residues
o Carboxypeptidase E – exoproteolysis of C-terminal basic residue
o Aminopeptidase – exoproteolysis of N-terminal basic residue
o Amidation of C-terminal glycines
o Acetylation of N-terminal
ACTH Processing
Pre-proopiomelanocortin (w/ signal peptide bound) –> proopiomelanocortin + signal peptide –> ACTH + beta-lipotropin –> gama-lipotropin + beta-endorphin
Calcitonin Genes
– different splicing mechanisms results in either calcitonin or CGRP
o Calcitonin – thyroid cells – involved in calcium metabolism
o CGRP – brain – involved with pain and vasodilator
o Neuropeptides – unique in that a given gene can give rise to a protein and a neuropeptide with completely different biological profiles
Clearance, Renewal of Neuropeptides
o Extracellular degradation by endo- and exopeptidases
o Renewal of neuropeptides relies on synthesis in the cell body
Neuropeptide Receptors
– G protein receptors with 7 transmembrane domains
Varying affinity for neuropeptides since some are not as stable as others
o Bradykinin: B1, B2
o Opiods – mu, delta, kappa
Neuropeptides can be Co-localized with NT
– released by the same neuron
o NPY – Norepinephrine – locus ceruleus
o Dynorphin – GABA – striatum
o CCK – dopamine – striatum
o Somatostatin – GABA – striatum
o VIP – ACh – parasympathetic post-ganglion
o CGRP – ACh – spinal motor
o Neurotensin – dopamine – substantia nigra
o Thyrotropin-releasing hormone (TRH) increases GABA-mediated transmission
o NPY inhibits glutamate action
Neuropoietic Cytokines
– help in producing neurons, oligodendrocyte, astrocytes from stem cell
o Interleukins 6 and10
o Leukemia inhibitory factors (LIF)
o Neuropoietin and cardiotrophin like cytokines
Neuropoietic Receptors
o Extracellular domain + Intraceullular domains which activate JAK-STAT and MAPK pathways
Neuropoietic Cytokines Function/Involved in:
o CNS development, neurogenesis o Neuronal/glial survival o Neuroinflammation o Activate responses after CNS injury o Stress responses o Participate in chronic pain
Pro-inflammatory cytokines
– not expressed in brain unless there is inflammation
o Interleukin-1
o Tumor necrosis factor
Chemokines
– neuroinflammatory modulators
o Induce chemotaxis in nearby responsive cells
o Considered pro-inflammatory and can be induced during an immune response to promote cells of immune system to a site of infection
o Exert biological effects by interacting with G protein-linked transmembrane chemokine receptors
Cytokines vs. Chemokines
o Cytokines – provide support for neuronal differentiation
o Chemokines – modulate responses to injury
Response to Injury
– monocyte chemoattractant protein 1 (MCP1) or CCL2 will attract monocyte/macrophages
Neurotrophic Factors and Functions
– small proteins that exert survival-promoting and trophic actions on neuronal (or nerve) cells; active in both CNS and PNS
Neuronal differentiation
Neuronal survival and maintenance
Neuronal repair/plasticity
o Include neurotrophins, neuropoietic cytokines, glial-cell derived NTFs, fibroblast growth factors, and insulin-like growth factors
Important Neurotrophins
o Nerve growth factor (NGF) – sympathetic and sensory neuron maturation; cholinergic neurons in brain; auditory neurons in inner ear; development of visual system
o Brain-derived neurotrophic factor (BDNF) – increases dendritic spine density
Biological Functions of Neurotrophins
o Multiple neurons of the CNS Basal forebrain acetylcholine – memory Nigro-striatal dopamine – movement Serotonin – anxiety, food intake Cortical glutamate – movement Cortical noradrenergic – depression o Auditory neurons of inner ear o Development of the visual system
Neurotrophin Receptors Activated by Nerve Growth Factor (NGF)
o Trks (tropomyosin-receptor-kinase) – high affinity receptors – induce cell survival, differentiation, and synaptic plasticity
o P75 – a low affinity receptor –induce cell death
Involves Pro-neurotrophins
Involved with injury
