TABLE 6

Melatonin receptor-mediated functional responses in native tissues

Modified from Dubocovich et al. (2003).

Function	Receptor	Signaling	Tissue	Approach	References
CNS
Inhibition—neuronal firing in the SCN	MT₁	Increase in K⁺ conductance?	SCN	MT₁-KO	Liu et al., 1997; Jin et al., 2003
Inhibition—PACAP-stimulated CREB phosphorylation	MT₁	cAMP Inhibition	SCN	MT₁-KO	von Gall et al., 2000
				MT₁MT₂-KO	Jin et al., 2003
Phase shift—circadian rhythm of neuronal firing rhythms in the SCN brain slice	MT₁	UNK	SCN	MT₁-KO	Liu et al., 1997; Dubocovich et al., 2005
	MT₂	PKC activation		4P-PDOT	Hunt et al., 2001
Phase shift—circadian rhythm of wheel activity	MT₁	UNK		MT₁-KO	Dubocovich et al., 2005
				MT₂-KO
				MT₁MT₂-KO
Inhibition—dopamine release from rabbit retina	MT₂	UNK	Rabbit retina	Correlation between antagonist K_B in retina and K_i values on MT₂ recombinant receptors	Dubocovich et al., 1997
Inhibition—long term potentiation	MT₂	cAMP/PKA Inhibition	Hippocampus	4P-PDOT	Wang et al., 2005
				MT₂-KO
				Luzindole
				4P-PDOT
Hypothalamic-Hypophyseal-Gonadal Axis
Inhibition—prolactin secretion	MT₁	UNK	Anterior pituitary	MT₁-KO	von Gall et al., 2002a
Regulation of Per1 gene expression	MT₁	cAMP Inhibition	Anterior pituitary	MT₁-KO	von Gall et al., 2002a
Inhibition—Testosterone secretion	MT₁	cAMP inhibition	Leydig cells in testis	Luzindole	Frungieri et al., 2005
				MT1 antibody
Inhibition—Cortisol secretion	MT₁	Corticotropin/CRH inhibition	Adrenal from Capuchin monkey	Luzindole	Torres-Farfan et al., 2003, 2004
Regulation of oxytocin receptor gene expression and contractility in uterus	MT₂	PLC, PKC activation	Human myometrium	4P-PDOT	Sharkey and Olcese, 2007; Sharkey et al. 2009
Regulation of photoperiodic information	MT₁	Type 2 and 3 deiodinase	Pars tuberalis	MT₁-KO	Yasuo et al., 2009
				MT₂-KO
				MT₁MT₂-KO
Cardiovascular
Vasoconstriction	MT₁	Activation of BK_Ca channel	Rat caudal artery	Luzindole	Krause et al., 1995; Geary et al., 1997, 1998; Viswanathan et al., 1997; Ting et al., 1999
			Cerebral arteries
Vasodilation	MT₂	UNK	Rat caudal artery	4P-ADOT	Doolen et al., 1998; Masana et al., 2002
				4P-PDOT
Immune
Increase—splenocyte proliferation (i.e., cell-mediated immunity)	MT₂	UNK	Spleen	MT₁-KO	Drazen and Nelson, 2001
Increase—serum anti-keyhole IgG concentrations (i.e., humoral immunity)	MT₂	UNK	T cells	MT₁-KO	Drazen and Nelson, 2001
Inhibition of leukocyte rolling	MT₂	UNK	Microvasculature	4P-PDOT	Lotufo et al., 2001
Metabolism
Inhibition—insulin secretion	MT₁	cAMP inhibition	Pancreatic β-cells	4P-PDOT	Peschke et al., 2000, 2002; Kemp et al., 2002; Mühlbauer et al., 2009
		GLP-1 inhibition		Luzindole
				MT₁-KO
				MT₂-KO
				MT₁MT₂-KO
Inhibition—insulin secretion	MT₂	cAMP Inhibition	Pancreatic β-cells	MT₁-KO	Mühlbauer et al., 2009
				MT₂-KO
				MT₁MT₂-KO
Increased leptin production	MT₁	cAMP	Epididymal adipocytes	4P-PDOT	Alonso-Vale et al., 2005
				Luzindole
Cancer
Inhibition—cancer cell proliferation	MT₁	cAMP	Breast tumor	4P-PDOT	Dauchy et al., 2003; Blask et al., 2005a,b
		Linoleic acid uptake	Rat hepatoma	Luzindole
		13-HODE production		S20928
Inhibition—cell proliferation	MT₂	cAMP	JAr cells	Luzindole	Shiu et al., 1999; Dauchy et al., 2003
		Linoleic acid uptake	Rat hepatoma	4P-PDOT
		13-HODE production

UNK, unknown/undetermined etiology; PKA, protein kinase A; CRH, corticotropin-releasing hormone; PLC, phospholipase C; GLP-1, glucagon-like peptide; 13-HODE, (±)-13-hydroxy-9Z,11E-octadecadienoic acid.