At a Glance

276Cellular Transmission of Signals from Extracellular Messengers11 Hormones and ReproductionHormones, neurotransmitters ( p. 55 andp. 82), cytokines and chemokines ( p. 94ff.)act as messenger substances (first messengers)that are transported to their respective targetcells by extracellular pathways. The target cellhas a high-affinity binding site (receptor) forits specific messenger substance.Glycoprotein and peptide messengers aswell as catecholamines bind to cell surface receptorson the target cell. Binding of the messengerto its receptor (with certain exceptions,e.g. insulin and prolactin; p. 280) triggerscertain protein-protein interactions (andsometimes protein-phospholipid interactions).This leads to the release of secondarymessenger substances (second messengers)that forward the signal within the cell. Cyclicadenosine monophosphate (cAMP), cyclicguanosine monophosphate (cGMP), inositol1,4,5-trisphosphate (IP 3), 1,2-diacylglycerol(DAG) and Ca 2+ are such second messengers.Since the molecular structure of the receptorensures that the effect of the first messengerwill be specific, multiple first messengers canuse the same second messenger. Moreover, theintracellular concentration of the second messengercan be raised by one messenger andlowered by another. In many cases, differenttypes of receptors exist for a single first messenger.G s-activating messengers. ACTH, adenosine (A 2Aand A 2B rec.), antidiuretic hormone = vasopressin (V 2rec.), epinephrine and norepinephrine (β 1, β 2, β 3adrenoceptors), calcitonin, CGRP, CRH, dopamine(D 1 and D 5 rec.), FSH, glucagon, histamine (H 2 rec.),oxytocin (V 2 rec., see above), many prostaglandins(DP, IP, EP 2 and EP 4 rec.), serotonin = 5-hydroxytryptamine(5-HT 4 and 5-HT 7 rec), secretin and VIP activateG s proteins, thereby raising cAMP levels. TRHand TSH induce partial activation.G i-activating messengers. Some of the abovemessenger substances also activate G i proteins(thereby lowering cAMP levels) using a differentbinding receptor. Acetylcholine (M 2 and M 4 rec.),adenosine (A l and A 3 rec.), epinephrine and norepinephrine(α 2 adrenoceptors), angiotensin II,chemokines, dopamine (D 2,D 3 and D 4 rec.), GABA(GABA B rec.), glutamate (mGLU 2–4 and mGLU 6–8rec.), melatonin, neuropeptide Y, opioids, serotonin= 5-hydroxytryptamine (5-HT l rec.), somatostatinand various other substances activate G i proteins.Effects of cAMP. cAMP activates type A proteinkinases (PKA = protein kinase A) which thenactivate other proteins (usually enzymes andmembrane proteins, but sometimes the receptoritself) by phosphorylation ( A4). Thespecific response of the cell depends on thetype of protein phosphorylated, which is determinedby the type of protein kinases presentin the target cell. Phosphorylation convertsthe proteins from an inactive to an active formor vice versa.cAMP as a Second MessengerFor a cAMP-mediated response to occur, thecell membrane must contain stimulatory (G s)or inhibitory (G i) G proteins (guanyl nucleotide-bindingproteins) ( A1). These Gproteins consist of three subunits—alpha (α S orα i), beta (β) and gamma (γ)—and are thereforeheterotrimers. Guanosine diphosphate (GDP) isbound to the α-subunit of an inactiveG protein. Once the first messenger (M) bindsto the receptor (Rec.), the M–Rec. complexconjugates with the G s-GDP (or G i-GDP)molecule ( A2). GDP is then replaced by cytosolicGTP, and the βγ-subunit and the M–Rec.complex dissociate from the α-subunit if Mg 2+is present ( A3). α s-GTP or α i-GTP remain asthe final products. Adenylate cyclase on the insideof the cell membrane is activated by α s-GTP (cytosolic cAMP concentration rises) andinhibited by α i-GTP (cAMP concentration falls; A3).Hepatic glycogenolysis, for instance, is dually increasedby cAMP and PKA. Glycogen synthase catalyzingglycogen synthesis is inactivated by phosphorylationwhereas glycogen phosphorylase stimulatingglycogenolysis is activated by cAMP-mediatedphosphorylation.Signal transduction comprises the entire signalingpathway from the time the first messengerbinds to the cell to the occurrence ofcellular effect, during which time the signalcan be (a) modified by other signals and(b) amplified by many powers of ten. A singleadenylate cyclase molecule can producenumerous cAMP and PKA molecules, which inturn can phosphorylate an enormous numberof enzyme molecules. The interposition ofmore kinases can lead to the formation of longkinase cascades that additionally amplify theoriginal signal while receiving further regulatorysignals.Hormone receptor defects, hormone therapy, phosphodiesterase inhibitors(e.g. sildenafil citrate)