FIGURE 3.

Intra- and intercellular modulation of melatonin synthesis. NE binds to the ɑ₁, ɑ₂, and β₁ adrenergic receptors on pinealocytes triggering a complex myriad of intracellular molecular cascades that eventually regulate melatonin synthesis. Pinealocytes may engage in autocrine and/or paracrine regulation via glutamate release via mGluR3. Pinealocytes may also form a tripartite synapse with astrocytes and postganglionic sympathetic terminals. Blue arrows, upregulating melatonin synthesis; red arrows, downregulating melatonin synthesis; black arrows, mixed or unclear effects on melatonin synthesis. 5-HT, 5-hydroxytryptamine; 5-HTP, 5-hydroxytryptophan; AA, arachidonic acid; AANAT, aralkylamine N-acetyltransferase; AC, adenylate cyclase; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ATP, adenosine triphosphate; ɑ₁-AR, ɑ₁-adrenoreceptor; ɑ₂-AR, ɑ₂-adrenoreceptor; BK_Ca2+, large-conductance Ca^2+–activated K⁺channel; CACC, Ca²⁺activated Cl^– channels; CaM, calcium binding protein calmodulin; cAMP, cyclic guanosine monophosphate; CBP, CREB-binding protein; cGMP, cyclic guanosine monophosphate; CRE, cAMP response element; CREB, cAMP response element binding protein; DAG, diacylglycerol; ER, endoplasmic reticulum; GC, guanylate cyclase; Glut, glutamate; iGluR1, ionotropic glutamate receptor 1; IP₃, inositol trisphosphate; MAPK, mitogen-activated protein kinase MAPK; Mel, melatonin; mGluR3, metabotropic glutamate receptor 3; mGluR5, metabotropic glutamate receptor 5; nAChR, nicotinic acetylcholine receptor; NAS, N-acetylserotonin; NE, norepinephrine; NF-kβ, nuclear factor kappa-light-chain-enhancer of activated β cells; NO, nitric oxide; NOS, nitric oxide synthetase; PDE, phosphodiesterase; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PLA₂, phospholipase A₂; SKCa²⁺, small-conductance Ca^2+–activated K⁺ channel; TNF- α, tumour necrosis factor – α; VDCC, voltage-dependent Ca²⁺ channels; β1-AR, β1-adrenoreceptor.