• mediates many hormonal messages
• made from ATP by adenylate cyclase (AC); [cAMP] = 10^-7 M, increased 2-100X upon AC activation
• 6 TM, cytoplasmic catalytic domain, two quasisymmetric regions req. for catalysis
• alpha of G_s stimulates
• alpha of G_i inhibits (cancel out G_s effect or lower from normal baseline levels)
• beta-gamma can either stimulate or inhibit (different isoforms)
• forskolin directly activates AC, cholera toxin indirectly through G_s
• cytosolic Ca⁺⁺ concentrations also control activity
• destroyed by phosphodiesterases (themselves inhibited by xanthine derivatives like theophylline, caffeine)
• turns on PKA, a tetramer of two catalytic (kinase, C) and two regulatory (inhibitory, R) subunits
• tetramer is inactive until the R-subunit binds cAMP and releases the C-subunits
• targets of PKA phosphorylation themselves are often kinases, so this forms a cascade
• Regulation by cAMP
• metabolic: lipid/carbohydrate metabolism, steroidogenic response to pituitary hormones
• electrophysiological: phoshorylate ion channels, turning them on or off (esp Ca⁺⁺)
• gene expression: (CRE-cAMP sens reg element in 5’ flanking, PKA phoshorylates CREB protein)

 cGMP as a Second Messenger

• 3 cGMP-Guanylate Cyclases (GC)
• (1) intrinsic membrane-receptor for ANF (atrial natriuretic factor) (smooth muscle/renal, large extracellular domain,probably dimerizes)
• (2) soluble, heme-binding GC regulated by NO (each dimer binds heme, NO increases activity)
• (3) membrane protein regulated by Ca⁺⁺ levels
• phosphodiesterases—some passive, others regulated
• rhodopsin activation of transducin (G_t) activates cGMP PDE for visual processing
• many protein kinases and ion channels are mediated by cGMP
• PKG: cGMP associated protein kinase (especially smooth muscle, regions of brain)
• PKG dependent protein phosphetase activates Ca⁺⁺-dependent K⁺ channels which cause hyperpolarization of plasma membrane, inactivation of voltage-dependent Ca⁺⁺ channels, and reduction of cytoplasmic Ca⁺⁺, leading to relaxation and vasodilation
• since NO from endothelial cells (paracrine) regulates cGMP levels, nitroglycerine is a vasodilator
• An Example: Visual Signal Transduction  
• retinal cells express a Na⁺/Ca⁺⁺ channel gated by intracellular cGMP (open when high cGMP)
• in the dark:
• no photoisomerization of rhodopsin or activation of transducin
• less PDE so lots of cGMP; Na⁺/Ca⁺⁺ channels open, causing depolarization
• in light:
• activate rhodopsin/transducin
• PDE on so cGMP down, channels close, cell is hyperpolarized
• less inhibitory neurotransmitters released, suppressing electrical activity in retinal cell neuronal targets