Trends in Pharmacological Sciences
Non-visual GRKs: are we seeing the whole picture?
Section snippets
GRK structure and distribution
There are three sub-groups within the GRK family. GRK1 (rhodopsin kinase) and GRK7 (cone opsin kinase) form one distinct sub-group that is only found in retinal cells. The non-visual GRKs divide into two sub-groups: the GRK2 subfamily, consisting of GRK2 (β-ARK1) and GRK3 (β-ARK2), and the GRK4 subfamily, consisting of GRK4, GRK5 and GRK6. GRK4 is predominantly found in the testes [19] and, to lesser extent, in some brain regions and the kidney 20, 21, whereas GRKs 2, 3, 5 and 6 are widely
Experimental approaches
In many studies the involvement of various GRKs in the regulation of GPCRs is often implied by overexpression of both receptor and kinases, usually in heterologous expression systems. Although this approach indicates that certain GPCRs can be substrates for several GRKs, it is limited because it fails to determine whether endogenously expressed GRKs regulate GPCR function. With this in mind, we focus here on studies in which manipulation of the activity of endogenous GRKs is the adopted
GRK4
Because of its limited distribution (Table 1) GRK4 has tended to be overlooked as a kinase that might regulate GPCRs other than those expressed in the testes. However, GRK4 appears to play a specific role in the regulation of GPCRs in tissues in which its expression is relatively high (e.g. cerebellar Purkinje cells 21, 28 and the renal medulla [20]). Studies using antisense oligonucleotides to reduce selectively the expression of GRK2 or GRK4 in rat Purkinje cells or human renal proximal
Does the regulation of non-visual GRKs provide clues to their specificity?
Although it is well established that agonist activation of GPCRs is a prerequisite for GRK-mediated phosphorylation, relatively little is known about the exact recruitment signals for individual GRKs. The simplest model that can be proposed is one where the conformational change following agonist binding exposes domains of the receptor to ‘random’ kinase phosphorylation and the kinase(s) responsible will be determined by kinase availability and localization 10, 45. However, this model seems
Potential therapeutic targets for selective GRK inhibition
Despite the use of heparin, Zn2+ and suramin as nonselective inhibitors directed at the ATP binding site, at present there are no specific inhibitors of individual GRK activity. This is perhaps surprising because GRK expression levels are known to change in several disease states [10], and could be considered to be logical molecular targets with respect to the pharmacological manipulation of GPCR responsiveness. Furthermore, there are several distinct structural differences between the GRK
Concluding remarks
Much new information regarding the phosphorylation and regulation of GPCRs by GRK2 and GRK3 and their role in GPCR signalling has been revealed during the past few years. More recent studies have started to indicate roles for GRK4, GRK5 and GRK6, both in transfected cell lines and in primary cells. However, it remains to be established whether the multiplicity of GRKs is related to the specificity or differential regulation of GPCR signalling or indeed other, yet to be defined, functions. The
Acknowledgements
Our work is supported by a Wellcome Trust Programme Grant (No. 062495). We would like to thank Mark Nash, Ken Young, Andrew Tobin and Eamonn Kelly (University of Bristol), for many valuable discussions.
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2021, Cellular SignallingCitation Excerpt :Indeed, the N-terminus contains a RGS domain that binds to GTP-bound Gαq proteins, thus recruiting GRK2 to agonist-bound GPCRs [21]. In addition, the C terminal tail of GRK2 contains a pleckstrin homology (PH) domain that has the capacity to interact with many different proteins including Gβγ subunits [21], which also promotes the recruitment of GRK2 from the cytoplasm to active GPCRs [21]. Indeed, overexpression of the C terminal tail of GRK2 blocked interaction of GRK2 and PI3K, suggesting that the C terminal tail, and most likely the PH domain, is required for PI3K binding [42].
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