how drugs act Flashcards
Superfamilies of Receptors
Ligand-Gated Ion Channels
— “ionotropic” receptors
* G-Protein Coupled Receptors
— “metabotropic” receptors, “7 trans-membrane spanning domain” receptors, “heptahelical” receptors, “serpentine” receptors
* Kinase-Linked & Related Receptors
— large and heterogeneous group
— single trans-membrane spanning domain
* Nuclear Receptors
— “steroid superfamily”
- Ligand-Gated Ion Channels structure
G-Protein Coupled Receptors structure
Kinase-Linked & Related Receptors structure
Nuclear Receptors structure
Receptor Subtypes
- receptors in given family generally occur in several molecular varieties or “subtypes”
— similar architecture
— significant differences in amino acid sequence
— often different pharmacologic properties
— nicotinic acetylcholine receptor subtypes occur in different brain regions and these differ from subtype in muscle
- different genes, different phenotypes of receptor subtypes
— different genes may encode for different subtypes
- same gene, different phenotypes of receptors subtypes
how is this possible?
big role in which class of receptors?
— variation may arise from alternative mRNA splicing
* single gene can give rise to more than one receptor isoform
* splicing can result in inclusion or deletion of one or more mRNA coding regions giving rise to short or long forms of protein
* big role in G-protein coupled receptors
— single nucleotide polymorphisms
* often results in different drug-receptor efficacy
Ligand-Gated Ion Channels
share features with what other structures?
additional name?
- share structural features with voltage-gated ion channels
- “ionotropic” receptors
Ligand-Gated Ion Channels examples
— nicotinic acetylcholine receptor (nAChR)
— GABA type A receptor (GABAA): inhibitory neurotransmitter
— glutamate receptors: excitatory neurotransmitter
nAChR; structure/mechanism
— best characterized of all cell-surface receptors
— pentamer: four different polypeptide subunits (5 total)
* 2 a, 1 b, 1 g, and 1 d, MW from 43K-50K each
* each subunit crosses plasma membrane 4 times
— acetylcholine binds sites on a subunits
— conformational change occurs
— transient opening of central aqueous channel
— Na+ flow from outside to inside cell: down electro-chemical gradient
— cell depolarizes
— all occurs in milliseconds
G-Protein Coupled Receptors
- largest superfamily of receptors
- “metabotropic” receptors
- 7 transmembrane spanning domains
G-Protein Coupled Receptors mechanism
- agonist binds to region inside receptor surrounded by 7 TM domains
- conformational change in cytoplasmic side
— spreads cytoplasmic side of 7 TM domains
— opens cavity in receptors cytoplasmic side
— cavity binds critical regulator surface of the G-Protein - G-Protein affinity for nucleotide GDP is reduced
— GDP dissociates - GTP binds
— GTP normally higher in concentration than GDP intracellularly - GTP-bound G-Protein dissociates from the receptor
- GTP-bound G-Protein engages downstream mediators (a.k.a. “effectors”)
G-Protein Coupled Receptors agonsit dissociation and g pro actvity?
dif effects in various tissues?
- agonist binds and dissociates rapidly
— a few milliseconds - activated GTP-bound G-proteins remain active much longer
— up to tens of seconds
— this produces significant signal amplification from one ligand-receptor interaction - heterogeneity of G-proteins allow for substantial diversity in GPCR signaling in various tissues
Opioid Pharmacology
* Agonists of Opioid Receptors
— heroin, morphine, oxycodone,
hydrocodone
Competitive Antagonists of Opioid
Receptors
— naloxone, naltrexone
Opioid m type receptors (mOR) strucutre
Opioid m type receptors (mOR) morphine effects
common side effect of this in GI
K+ out (beta/gamma) and Ca2+ channel(alpha) antagonized=hyperpolarize
can cause constipation in GI
naloxone effect
comp antagonist of morphine= binds same site, can be overwhelmed with increased morphine
naloxone and morphine together and effect on respiratory rate, why useful?
can be used with suspected opiod OD