There is increasing evidence for non-genomic effects by TH (2,7) in addition to the transcriptional effects mediated by nuclear TRs. Although there is continuous shuttling of a small amount of TRs between the cytoplasm and nucleus , these non-genomic effects are most likely mediated by cellular binding proteins other than TRs. Evidence supporting this notion comes from the rapid time course of some TH effects (thus precluding transcription and protein synthesis), utilization of membrane-signaling pathways such as kinases or calmodulin, lack of dependence on the presence of nuclear TRs, and structure-activity correlations by TH analogs that are different than those observed for nuclear TRs . Several non-nuclear sites for TH binding have been identified in various cell systems although their functional significances are not well characterized. Some of these include: plasma membrane associated T3 transporters, calcium ATPase, adenylate cyclase, and glucose transporters ; an endoplasmic reticulum associated protein, prolyl hydroxylase; and monomeric pyruvate kinase .

TH also has profound effects on mitochondrial activity and cellular energy state . A 43 kD protein has been described in mitochondria which also could bind to TREs and could be recognized by antibodies against the TRα ligand-binding domain . Recently, it has been shown that TRβ can interact with the p85 subunit of PI3K and activate the PI3K-Akt/PKB signaling cascade; thus, the small subpopulation of cytosolic TRβ may be involved in cell signaling . This PI3K activation by T3 leads to both direct and indirect effects on the transcription of several genes involved in glucose metabolism and provides a mechanism for cross-talk between TH and cell signaling pathways .

Recently, integrin α Vβ 3, has been identified as a plasma membrane TH-binding site . Previously, T4, but not T3, was shown to promote actin polymerization and integrin interaction with laminin in neural cells . Additionally, both T4 and T3 activated mitogen-activated protein kinase (MAPK) activity, and led, among other events, to phosphorylation of TRβ (167). Using a chick chorioallantoic membrane (CAM) system, Davis et al. showed that both T4 and T3 stimulated angiogenesis. Since integrin α Vβ 3 is involved in angiogenesis, T4 and T3 binding to it was examined, and T4 was found to bind to integrin α Vβ 3 with high affinity. Tetraiodothyroacetic acid (tetrac) and antibodies against laminin blocked T4 binding. Moreover, siRNAs against the integrin α V or β 3 subunits blocked MAPK activation by TH. These findings suggest that TH activates the MAPK cascade and stimulates angiogenesis via TH binding to integrin α Vβ 3.