Autonomic Nervous Systems
Dopamine, epinephrine, and histamine are important neurotransmitter agonists. When these ligands interact with their cellular receptors they elicit a response by:
|A||Activating adenylyl cyclase, leading to increased intracellular cAMP levels|
|B||Activating phospholipase C|
|C||Inducing or inhibiting synthesis of ligand-specific intracellular proteins|
|D||Regulating intracellular second messengers through G protein-coupled receptors|
a. The key concept is that these very important agonists, and many others, “transduce” their signals and eventually change a characteristic of cell function (cause a response) through G proteins—a family of guanine nucleotide-binding proteins.
b. These ligands bind to the extracellular face of the transmembrane protein.
c. The various G proteins (e.g., Gi, Gq, Gs) bind to intracellular portions of the receptor.
d. They then couple the initial ligand interaction to the eventual response through a series of effector enzymes or enzyme systems that are G protein-regulated.
e. For example, adenylyl cyclase can be activated, catalyzing the formation of cAMP that then activates one or several kinases that phosphorylate specific intracellular proteins.
f. But the actual steps that occur after ligand binding depend on what the ligand is, what specific G protein is involved, and which kinases are activated and what proteins they phosphorylate. And what happens (i.e., what the response is) depends on all of the above and, of course, which cell type is being affected.
g. For example, activation of adenylyl cyclase and increased cAMP levels may occur in one system, but the opposite may occur in another. Some signal transduction pathways involve phospholipase C, others do not. A calcium channel may be affected in one system and a potassium channel (or no ion channel) in others.
h. By way of review, recall that there are three other main mechanisms or pathways for signal transduction about which we have reasonable knowledge.
i. One mechanism or pathway uses a receptor protein that spans the cell membrane, but G proteins are not involved. On the inner membrane face, it possesses enzymatic activity that is regulated by the presence or absence of ligand bound to the extracellular face of the protein.
j. The tyrosine kinase pathway is an example, and the overall pathway is responsible for the activity of various growth factors, including insulin.
k. Another is used by very lipid-soluble ligands that cross cell membranes easily and act on some intracellular receptor (e.g., glucocorticosteroid), which act in the nucleus and, through interaction with heat-shock protein (hsp9O), eventually alters changes in transcription of specific genes.
l. The third involves transmembrane ion channels, the “open” or “closed” states of which are controlled by ligand binding to the channel. This process applies to some of the important neurotransmitters, especially those in the brain (GABA, the main inhibitory neurotransmitter) and such amino acids as glycine, which exert “excitatory” actions. The nicotinic receptor for ACh fits in this category too.