Summers
- Kandel, Schwartz and Jessell:
Read pages 219-222 for this lecture
acronyms
end
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Summers |
Neurobiology |
text: Principles of Neural Science - Kandel, Schwartz and Jessell: Read pages 219-222 for this lecture acronyms end |
XXV. Receptors back to XVIII. Vesicles and transmitter release
A. membrane spanning proteins
1. often multiple peptides
a. multiple genes
2. two types
a. ligand binding directly gates ion channels
b. ligand binding activates 2nd messenger systems
i. may activate ion channels or other cellular machinery
c. some transmitters bind to both types
i. e.g. ACh
B. Acetylcholine receptors
1. Nicotinic have 5 protein subunits: a (2), b, g, d
a. 4 distinct but related genes
b. each subunit contains 4 membrane spanning protein helicies
i. number 2 helix always to the center
c. subunits together make up a Na+/K+ ion channel,
with the channel in the center
i. ACh bound to each a-subunit opens the channel by changing the
configuration of the proteins
ii. #2 helicies form the portions that open
d. excitatory at skeletal muscle, on postganglionic parasympathetic and
sympathetic neurons, and in the brain
i. associated with actions with rapid conduction, rapid information
transfer
e. activated by nicotine, blocked by curare
f. more like other ligand-gated ion channels (e.g. GABAA)
than like the muscarinic receptors
2. Muscarinic
a. G protein-coupled receptors activated by muscarine (mushrooms)
and blocked by atropine (deadly nightshade)
i. found in parasympathetically innervated cardiac and smooth
(e.g. intestine, iris) muscle, salivary, tear, and sweat glands,
and in cortical and subcortical neurons
b. G protein-coupled receptors are based on a core of 7 membrane
spanning helices
i. but the membrane spanning segments do not form an
ion channel
ii. rather, cationic and relatively hydrophobic ligands
(neurotransmitters) like ACh, bind to a site within
the bundle of helices
(1) protein ligands will require an extracellular domain
for binding
c. binding stimulates G (from GTP) protein activated/inhibited
2nd messenger cascade
i. 2nd messengers may activate ion channels, enzyme systems
(protein kinases), and/or DNA
d. receptor subtypes
i. in different cells or tissues a single ligand/transmitter can
stimulate different G proteins to initiate distinct 2nd
messenger responses
ii. M1, M3, & M5 acitvate Gp = phospholipase C (activates)
(1) muscarinic receptors have excitatory actions in the
gastrointestinal tract
iii. M2 & M4 activate Gi = inhibitory (AC)
(1) muscarinic receptors have inhibitory actions on the heart
e. binding may also stimulate G protein activated ion channel gating
i. GK+ opens K+ channels and closes Ca++ channels
C. Receptor superfamilies for small molecule transmtters
1. ionotropic = receptor ionophores = ligand-gated ion
channels = class I = fast
a. nicotinicACh, GABAA, APMAGlu, KAGlu, NMDAGlu,
5-HT3 & Gly-R
b. all have similar structure & function
i. utlize the same protein subunits (a, b, g, d sometimes r)
ii. separate but closely related genes for each subunit
2. 7 helix - inverted cone receptors coupled to G protein
= class II = slow (seconds to min) = modulatory
a. M1-5, DA1-5, a1A-D,2A-C & b1,2,3 adrenergic,
5-HT1A,B,D,E,2A-C,4,5A,B,6,7, mGlu-R1-7, H1-3
b. very similar structure = similar genes
D. GABA receptors
1. GABAA
a. postsynaptic, on central and sympathetic neurons
b. activates Cl- ion channel: inhibitory
i. central channel surrounded by 5 protein subunits
(1) a, b, g, d, r and subtypes of these subunits
(a) at least 15 related genes
c. b binds GABA
i. a binds benzodiazepines,
but g necessary for modulatory action
(1) benzodiazepines (like valium) frequency of
channel opening (not conductance or duration)
ii. b binds barbiturates
(1) barbiturates ¯ frequency, but duration
2. GABAB
a. presynaptic autonomic and central nerve terminals
i. also inhibitory, but not via Cl- conductance
(1)GK+ ® K+ and/or ¯ Ca++ conductance
3. GABAC
a. opens Cl- and Ca++ channels in the retina
5. GABA reuptake receptors
a. Na+ coexchange
E. Glycine
1. also directly gated: includes a, b of 5 subunits; Cl- channel: inhibitory
a. Gly/strychnine bind to a
F. Glutamate/Asp
1. Excitatory: AMPA, KA open Na+ channels
(non-specific cation so K+ & Ca++ too)
a. NMDA opens Ca++ (also non-specific)
i. NMDA act in conjuction with AMPA or KA
ii. NMDA/AMPA or NMDA/KA held together in place
by post-synaptic density proteins
(1) like PSD95, GKAP, Shank
2. metabatropic: mGlu-R1&5 activate Gp
a. mGlu-R2-4,6,7,8 inhibit cAMP via Gi
G. DA
1. G protein mediated: DA1 type = DA1&5 activate Gs,
(G protein stimulates AC and cAMP)
2. DA2 subtypes = DA2,3,4: Gi
H. Adrenergic (NE and Epi)
1. a1 & a2 bind Epi > NE ; b1 & b2 bind Epi > NE
a. a1: Gp in brain and blood vessels
b. a2: Gi in presynaptic neuronal terminals throughout brain
i. inhibitory autoreceptors: negative feedback
c. b1 & b2: Gs in cerebrum and cerebellum
I. 5-HT
1. Gi: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F
2. Gp: 5-HT2A, 5-HT2B, 5-HT2C, 5-HT2D
3. Gs: 5-HT4, 5-HT6, 5-HT7
4. 5-HT3 gates non-selective cation channel
J. Histamine Receptors
1. H1 ® Gp ® PLC ® PIP2 ® IP3 ® increase Ca++
a. hormone release, smooth muscle contraction
2. H2 ® Gs ® AC ® cAMP ® PKA
a. smooth muscle relaxation
3. H3 ® G?
a. autoreceptors in cortex
b. inhibit release of monoamines and peptides from
brain and peripherial tissue
K. Peptide Receptors (~104±1/cell)
1. Extracellular region = binding site, N-terminal portion,
potentially glycosylated
a. often many cysteines, with S-S bonds forming rigid pockets ®
transmitter/modulator binding
b. also link receptor chains (same or different receptors)
2. a-helical transmembrane proteins and intracellular protrusions
3. G protein coupled ® 2nd messenger systems
L. Steroids have neuromodulatory roles via central receptors
1. bind to cytoplasmic/nuclear receptors which bind to and activate DNA
transcription directly
2. also bind to membrane receptors
a. P, B - receptors specifically for the steroid
b. GABAA, NMDA receptors bind steroids
M. Law of Mass Action
k1 = association rate constant
k1
1. L + R ¨ LR k2 = dissociation rate constant
k2
[L] = [free ligand]
[R] = [free receptor]
2. Kd = k2/k1 = [L][R]/[LR] [LR] = occupied binding sites
Kd = dissociation equilibrium const.
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