Most extracellular signals do not enter the cell directly. They bind receptors on the outside of the plasma membrane, which transmit the signal to the inside. Three main classes of cell surface receptors dominate the MCAT:
GPCRs (Reviewed from Chapter 3)
Seven transmembrane alpha helices. Coupled to heterotrimeric G proteins inside. Ligand binding triggers GDP-GTP exchange on the Gα subunit, which dissociates from Gβγ and activates downstream effectors (adenylyl cyclase, phospholipase C, etc.). Major second messengers: cAMP (Gs), decreased cAMP (Gi), IP3/DAG/Ca2+ (Gq).
Single transmembrane protein. The cytoplasmic domain is a tyrosine kinase. Ligand binding dimerizes two receptor monomers, triggering cross-phosphorylation on specific tyrosine residues. Phosphotyrosines become docking sites for SH2-domain proteins that activate downstream pathways (Ras/MAPK, PI3K/AKT, PLCγ).
Receptors that double as ion channels. Ligand binding opens or closes the channel directly. Fast electrical response (milliseconds).
Examples:
Nicotinic acetylcholine receptor: nonselective cation channel at the neuromuscular junction. Opening depolarizes the muscle cell.
GABA-A receptor: Cl- channel in the CNS. Opening hyperpolarizes neurons (inhibitory). Target of benzodiazepines and many anesthetics.
NMDA receptor: Ca2+ and Na+ channel. Requires both glutamate and membrane depolarization to open. Critical for learning and memory (long-term potentiation).
What are the three main classes of cell surface receptors, and which is fastest?
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(1) Ligand-gated ion channels - fastest, milliseconds (direct electrical effect). (2) GPCRs - seconds (second messenger cascades). (3) Receptor tyrosine kinases - minutes to hours (phosphotyrosine signaling and transcriptional changes). Steroid hormone receptors (intracellular, not surface) are slower still.
How does a receptor tyrosine kinase activate itself upon ligand binding?
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Ligand binding dimerizes two receptor monomers. The intracellular kinase domains cross-phosphorylate each other on tyrosine residues. The resulting phosphotyrosines serve as docking sites for SH2-domain-containing proteins (e.g., Grb2), initiating downstream cascades like Ras/MAPK and PI3K/AKT.
Why is the GABA-A receptor considered inhibitory in the CNS?
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GABA-A is a ligand-gated Cl- channel. When GABA binds, the channel opens and Cl- flows into the cell (because ECl is near or below the resting potential). The influx of negative charge hyperpolarizes the cell, making it less likely to fire an action potential - inhibitory. Benzodiazepines and barbiturates enhance GABA-A activity, increasing this inhibition.
