S1P Signaling Pathways in Pathogenesis of Type 2 Diabetes

Table 1

Signaling pathways mediated by S1PR_1-5.

	Pathway	People	Time	Effect
S1PR1	Inhibit AC through Giα [107]	Okamoto et al. [107]	1998	(1) Reduce cyclic adenosine phosphate (cAMP), promote cell proliferation, and increase survival/prevent cell apoptosis; (2) Increase intracellular free calcium and promote insulin secretion at high glucose levels [108]; (3) Promote erythrocyte migration, enhance endothelial barrier function and induce vasodilation, and reduce the occurrence of diabetic macrovascular complications [109]
	Activate PLC via Giβγ, Ras-MAPK [107], PI3K/Akt [110]	Lee et al. [110]	1999
S1PR2	Activate PI3K through Giβγ, Ras	Kon et al. [111]	1997	(1) Promote cell proliferation, increase survival/prevent cell apoptosis, and increase intracellular free calcium; (2) Inhibit migration, reduce endothelial barrier function, and induce vasoconstriction; (3) Increase cyclic adenosine phosphate (cAMP); (4) Mediate the occurrence of diabetic retinopathy [112]
	Activate PLC via Gq
	Activate Rho via G13
	Activate AC [111], JNK, and p38 [23]	Gonda et al. [23]	1999
S1PR3	Inhibit AC through Giα	Okamoto et al. [113]	1999	(1) Reduce cAMP; (2) Increase intracellular free calcium, promote cell proliferation, and promote insulin secretion at high glucose levels [108]; (3) Reduce cytokine-induced islet β cell apoptosis [32, 114]; (4) Promote endothelial cell migration and induce vasodilation; (5) Mediate local inflammation of the kidney in diabetic nephropathy [17]
	Activate PLC, PI3K, and Ras via Giβγ
	Activate PLC via Gq
	Activate Rho via G13 [113]
	Activate AC [115]	Malek et al. [115]	2001
S1PR4	Activation of Cdc 42 through Giβγ [116]	Kohno et al. [116]	2003	(1) Mainly expressed in lymphoid tissue, lungs, the brain (especially oligodendrocytes), white blood cells, and the spleen [117]. The role is not clear.
	PLC [118]	Yamazaki et al. [118]	2000
	ERK [119]	Van Brocklyn et al. [119]	2000
	Activate Rho via G12/13 [38]	Graler et al. [120]	2003
S1PR5	Inhibit AC through Giα [121]	Im et al. [121]	2000	(1) Mainly expressed in lymphoid tissue, lungs, the brain (especially oligodendrocytes), white blood cells, and the spleen [117]. The role is not clear.
	Inhibit ERK, activate JNK, couple G12 [115]	Malek et al. [115]	2001