Increased expression of G-protein-coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules

Abstract

G-protein-coupled receptor kinases (GRKs) are implicated in the pathophysiology of human diseases such as arterial hypertension, heart failure and rheumatoid arthritis. While G-protein-coupled receptor kinases 2 and 5 have been shown to be involved in the desensitization of the rat thyrotropin receptor (TSHR), their role in the pathophysiology of hyperfunctioning thyroid nodules (HTNs) is unknown. Therefore, we analyzed the expression pattern of the known GRKs in human thyroid tissue and investigated their function in the pathology of HTNs. The expression of different GRKs in human thyroid and HTNs was measured by Western blotting. The influence of GRK expression on TSHR function was analyzed by coexpression experiments in HEK 293 cells. We demonstrate that in addition to GRKs 2, 5 and 6, GRKs 3 and 4 are also expressed in the human thyroid. GRKs 2, 3, 5 and 6 are able to desensitize the TSHR in vitro. This GRKinduced desensitization is amplified by the additional over-expression of -arrestin 1 or 2. We did not find any mutations in the GRKs 2, 3 and 5 from 14 HTNs without TSHR mutations and G s mutations. The expression of GRKs 3 and 4 was increased in HTNs independently from the existence of TSHR mutations or G s mutations.In conclusion, the increased expression of GRK 3 in HTNs and the ability of GRK 3 to desensitize the TSHR in vitro, suggest a potential role for GRK 3 as a negative feedback regulator for the constitutively activated cAMP pathway in HTNs.

Decreased Expression of G-Protein Coupled Receptor Kinase 2 in Cold Thyroid Nodules

“…demonstrated in differentiated thyroid carcinoma cells (Metaye et al, 2002). In previous investigations we found an expression of GRKs 2 ± 6 in human thyroid tissue (Voigt et al, 2004). We could demonstrate that GRK 2, 3, 5 and 6 are able to desensitize the TSH receptor in vitro by coexpression of the different GRKs with the TSH receptor in HEK 293 cells and we found an increased expression of GRK 3 and 4 in hyperfunctioning thyroid nodules (HTNs) compared to their surrounding thyroid tissue (Voigt et al, 2004).…”

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

“…Moreover, it is important to note that a particular GRK does not have to be the most prominently expressed GRK in a tissue to be crucial for a specific GPCR signaling regulation as its cellular localization and activity are key measures determining GPCR-GRK interactions. More recently, GRK3 and GRK4 have been described to be present in the thyroid nodules and to be upregulated in hyperfunctioning thyroids, which may also indirectly impact cardiac function (262).…”

Immunohistochemical detection, regulation and antiproliferative function of G-protein-coupled receptor kinase 2 in thyroid carcinomas

“…A key role for GRK2, GRK5, and GRK6 was first demonstrated in the TSH receptor homologous desensitization using a rat thyroid cell line (FRTL-5; Iacovelli et al 1996, Nagayama et al 1996a). Subsequently, GRK3 was also shown to desensitize the TSH receptor in HEK 293 cells (Voigt et al 2004). A predominant role for GRK5 (Metaye et al 2002) and GRK3 (Voigt et al 2004) has been suggested in differentiated thyroid carcinomas (DTC) and hyperfunctioning thyroid nodules respectively.…”

“…A predominant role for GRK5 (Metaye et al 2002) and GRK3 (Voigt et al 2004) has been suggested in differentiated thyroid carcinomas (DTC) and hyperfunctioning thyroid nodules respectively. Furthermore, these findings were reinforced by the detection of GRK proteins in human thyroid tissues (Voigt et al 2004), with a major expression of GRK2 and GRK5 (Nagayama et al 1996a, Metaye et al 2002.…”