Summers |
Neurobiology |
text:
Principles of Neural Science - Kandel, Schwartz and Jessell: Read pages 289-296 for this lecture acronyms end |
XXIII. Neuromodulators and Neuropeptides back to XXI. Neuroactive Steroids A. Neuromodulators alter the action of transmitters 1. enhancing or reducing transmitter effectiveness, but not directly stimulating neural transmission a. transmitter synthesis, release, receptor binding and unbinding, reuptake and catabolism are affected by different neuromodulators 2. many hormones are neuromodulators a. ACTH and cortisol/corticosterone stimulate TH, DBH, and PNMT i. stress hormones stimulate the production of sympathetic neurotransmitters 3. excitatory/inhibitory amino acid transmitters have neuromodulatory roles B. Neuropeptides often act as neuromodulators 1. more than 50 a. many are hormones 2. as transmitters/modulators peptides are released close to the site of action 3. actions in the CNS may be similar to peripheral hormonal action a. e.g. endorphins and enkephalins are localized in regions of the brain associated with pain b. e.g. MSH, ACTH, & b-endorphin regulate complex central responses to stress c. e.g. GnRH and Oxy affect sexual/reproductive behavior 4. may act as a conventional transmitter, cause excitation, inhibition or both a. and have modulatory effects such as altering the time course or magnitude of transmitter release, altering receptor binding or reuptake b. and have combined effects to modulate behavior, sensibility, and emotion C. Families of Neuroactive Peptides 1. Members of each family are structurally related a. stretches of similar amino acid sequences i.\ derived from related genes (1) divergent or convergent evolution (2) phylogenetically conserved 2. structurally related peptides may have similar functions a. may mediate the same or similar physiological processes i. may bind with limited affinity to the other's receptor 3. Opioids a. enkephalins, dynorphins, endorphins 4. Neurohypophyseal a. AVP, Oxy, neurophysins 5. Tachykinins (rapid, move) a. substance P, bombesin, substance K (neurokinin A) 6. Secretins a. secretin, glucagon, VIP, GIP, GHRH 7. Insulins a. insulin, IGF1, IGF2 8. Somatostatins a. somatostatin, PP (pancreatic polypeptide) 9. Gastrins a. gastrin, CCK 10. functions within a group may be dissimilar D. Several Neuroactive peptides may be encoded on a single continuous strand of mRNA 1. large precursor molecule a. e.g. POMC = proopiomelanocortin i. aMSH, ACTH, b-endorphin 2. no high affinity reuptake mechanism a. enzymatic degradation necessary for removal 3. post-release cleavage products may provide signals a. catabolism does not end signal b. catabolite may effect pre- and post-synaptic cells c. fine tune interactions between peptides and other coexisting transmitters E. Peptides and small-molecule transmitters coexist in the same synapse = colocalization 1. may be coreleased a. cotransmission 2. vesicles that release peptides differ from those of small-molecule transmitters 3. examples:
transmitter | peptide | location |
5-HT | substance P | raphe |
TRH | ||
enkephalin | ||
GABA | somatostatin | cortex & hippocampus |
NE | neurotensin | LC |
DA | CCK | VTA |
neurotensin |
F. example of neuropeptide as neuromodulator: Neurotensin (NT) 1. widely expressed in CNS and periphery (small intestine) 2. Synthesis: cleaved from 170 aa prohormone a. 1 exon includes NT and Neuromedin (NMn) b. related peptides in birds (LANT6) and frogs (xenopsin) 3. enzymatic inactivation: metalloendopeptidases a. no high affinity reuptake process (like other peptides) 4. Internalization a. bound to autoreceptor i. retrograde transport like neurotrophins b. modify cell action i. e.g. ñ DA cell TH expression in striatum G. example 2: CRF effects in limbic system 1. CRF containing circuits from amygdala and hypothalamus innervate extensive group of neurons in pons, medulla, cortex and amygdala (interneurons) a. stress-related circuitry i. hormonal: CRH (=CRF) from PVN ® ñ ACTH from pituitary ® ñ B/F from adrenal ii. neuroactive: CRF from central Amygdala (CeA) ® ñ GABA in CeA ® ¯ GABA in BNST (bed nucleus of stria terminalis) ® ñ PVN (1) CeA CRF ® ñ LC ® ñ NE (2) CeA CRF ® ¯ raphe ® ¯ 5-HT (a) but effects of CRF on 5-HT in terminal regions like hippocampus or striatum can be dose or exposure dependent (i) in striatum low dose® ¯ 5-HT high dose® ñ 5-HT 2. two receptor types:CRF-R1 and CRF-R2 & 2a a. both activate Ca++ channels via Gs ®AC ... but ... b. CRF-R1 are excitatory i. potentiate Glu c. CRF-R2 are inhibitory d. distribution determines effect i. relation to Glu or GABA 3. CRF ® ñ APs of cells that fire in bursts: hippocampal pyramidal cells a. can promote seizure-like activity of limbic system 4. anxiogenic + stimulates spontaneous locomotion
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