Arrestins Come of Age: A Personal Historical Perspective - Progress in Molecular Biology and Translational Science - page 6

limited to the retina, and GRK4 also has a very restricted distribution
(reviewed in Refs. 28,29 ).
John Tesmer has solved crystal structures of several members of the fam-
ily, all of which share a conserved central catalytic domain flanked by two
more divergent regulatory domains. 30,31 In GRK2 and 3, the carboxyl ter-
minal domain is a PH or pleckstrin homology domain that binds free G bg as
a means of stimulus-dependent translocation to the plasma membrane from
the cytosol. GRKs 5 and 6, however, are constitutively membrane bound
through other mechanisms. 28
5. ARRESTINS AND DESENSITIZATION
Both visual arrestin and b -arrestin1 were discovered in the specific
context of their ability to functionally turn off or desensitize rhodopsin or
b 2AR signaling, respectively. When we cloned b arr1 and 2, we took as
the ultimate validation of the cloned molecules' functionality the ability
of the authentic recombinant materials to block b 2AR activation of G s ,in
reconstituted systems. Discovery of GRK2 and the b -arrestins capped my
20-year search to understand how stimulation of the b 2AR (and presumably
the other GPCRs) led to a rapidwaning of the response to further stimulation.
I had been particularly interested in the so-called homologous desensitization
wherein stimulation of the receptor desensitizes only that receptor and not
others (the latter phenomenon being referred to as heterologous desensitiza-
tion). 32 The GRK- b arr mechanism is a major mediator of homologous
desensitization, while phosphorylation of the receptor by second messenger
kinases such as PKA and PKC is a major mechanism of heterologous desen-
sitization of the receptors. 32,33 Numerous other mechanisms can lead to
desensitization of GPCRs, especially the heterologous form.
6. ARRESTINS AND ENDOCYTOSIS
That arrestins might be involved in the very general phenomenon of
agonist-induced GPCR endocytosis was initially suggested by evidence that
receptor phosphorylation, in particular, by GRKs, played a role in this
process. 34 Then it was demonstrated that b -arrestins promoted receptor
internalization when overexpressed in cells and that “dominant negative”
b -arrestin mutants inhibited this process. 35 Shortly thereafter, it was demon-
strated that b -arrestins can bind to clathrin, immediately offering a potential
mechanism for this new function of arrestins. 36 Subsequently, it has been