Channel-linked Receptors aka: ligand-gated channels a receptor type seen in synaptic transmission rapid response (ms) limited response –depolarization –hyperpolarization –stabilization of membrane potential inhibition of depolarization inhibition of hyperpolarization Fig , Alberts et al., Molecular Biology of the Cell

Non Channel-linked Receptors “second messenger” systems –“first messenger” = extracellular chemical signal –“second messenger” = intracellular signal slower responses than channel-linked receptors > 100 ms amplification of signal varied responses –protein phosphorylation –opening or closing of a channel

First Messenger Second Messenger(s) Alberts et al., Molecular Biology of the Cell, 3 rd ed. Second Messenger Systems

Major Responses protein phosphorylation (regulation of enzyme activity) regulation of ion channels Fig Ganong Fig Ganong “Physiologic effects” can include changes in gene expression.

G-protein Systems GTP required for function ligand binds to receptor activated receptor activates G protein activated G protein activates (or inhibits) an enzyme [or a channel] Figs and Alberts et al., Molecular Biology of the Cell

Two Examples of G-protein Systems adenylate cyclase pathway phospholipase C pathway phospholipase C adenylate cyclase second messenger IP 3 Alberts et al., Molecular Biology of the Cell, 3 rd ed. (cyclic AMP)

adenylate cyclase pathway (see Fig ) phospholipase C pathway (see Fig ) phosphodiesterase Adenylate cyclase Fig Ganong Fig Ganong PIP 2 = a specific phospholipid PLC = phospholipase C IP 3 = inositol trisphosphate DAG = diacylglycerol PKC = protein kinase C CaBP = calcium-binding protein Two Examples of G-protein Systems (e.g., calmodulin) Note: G-protein-linked receptors are serpentine receptors that are “7-pass” transmembrane proteins

Enzyme-linked Receptors The receptor is also an enzyme. –e.g., The receptors for insulin and various growth factors have tyrosine kinase activity. The receptor directly activates an enzyme. –e.g., The receptors for growth hormone and various cytokines activate a peripheral membrane protein that is a tyrosine kinase. Fig , Alberts et al., Molecular Biology of the Cell

G-protein Systems and Catalytic Receptor Pathways Overlap Fig Alberts et al., Molecular Biology of the Cell

The Number of Receptors on the Cell Surface is Regulated. up regulation  # of chemical signals   # of receptors e.g., denervation hypersensitivity down regulation  # of chemical signals   # of receptors e.g., drug tolerance Both up regulation and down regulation are typically negative feedback processes. Fig

Receptor Theory Alberts et al., Molecular Biology of the Cell

Synaptic Transmission (e.g., cholinergic synapse)  The action potential arrives at axon terminal (“synaptic knobs”). The “passive” depolarization of the end bulb causes voltage-gated Ca ++ channels to open.  The increase in cytosolic Ca ++ stimulates the exocytosis of synaptic vesicles. Fig Fig. 4-4, Ganong    Synaptic cleft

Synaptic Transmission  The contents of the synaptic vesicle are chemical signals (neurotransmitter molecules) that diffuse across the synaptic cleft (a distance of nm). The neurotransmitters reach the postsynaptic cell, where they bind to receptors, (e.g., channel-linked receptors, Fig

Synaptic Transmission  (cont’d) which cause the channels to open allowing, e.g., Na + to enter the postsynaptic cell).  The entry of Na + would cause a graded depolarization (e.g., EPSP) of the postsynaptic membrane. This graded depolarization can trigger an action potential “downstream.” Fig