Biology Reference
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unlike arrestin, they are ubiquitously expressed. Today, we know there is a
fourth member of the family called X-arrestin or arrestin4, expression of
which also seems largely limited to the retina.
22
As described in subsequent
chapters, all members of this small family share the same fold consisting of
two domains comprised almost entirely of antiparallel
b
-sheets connected
by a hinge region and have many shared, though also individual, properties.
23
A brief word about the somewhat confusing nomenclature in this field
seems in order. The genesis of the name arrestin for the visual “48K” pro-
tein, as a molecule which arrests signaling, is described above. Hence, when
we cloned the second member of the family as a protein which worked in
concert with
b
ARK to desensitize the
b
2AR, it seemed natural to name it
b
-arrestin.
20
At the time, we had no evidence that this mechanism of recep-
tor regulation was a very general one. Two years later, in September 1992,
we reported the cloning of a third family member and named it
b
-arrestin2.
21
The following summer, in July of 1993, Benovic's group
reported the cloning of the same molecule (albeit from cow rather than
rat) and the fact that there were two alternatively spliced forms with or with-
out an 11-amino acid insert.
24
His group proposed that
b
arr1 now be
renamed arrestin2 and that
b
-arrestin2 be renamed arrestin3. Over the sub-
sequent 20 years, both sets of terminology have persisted and are used
interchangeably.
Further evidence of the conserved nature of the receptor “turnoff”
mechanism involving GRKs and arrestins was our demonstration also in
1986 that rhodopsin kinase could phosphorylate the agonist-occupied
b
2AR and that
b
ARK could phosphorylate light-bleached rhodopsin, albeit
each with much slower kinetics than their natural substrates.
25
In 1988, we cloned the cDNA for
b
ARK and realized that it was the
founding member of a novel subfamily of kinases, most closely related to
the AGC kinase family of second messenger-dependent kinases.
26
After per-
suading Kris Palczewski to purify a preparation of rhodopsin kinase over his
Christmas holiday in 1989 before moving to Seattle from his
post doc
in Paul
Hargrave's lab, we were able to obtain some amino acid sequence on this
protein, which allowed us to design probes to clone its cDNA. Rhodopsin
kinase turned out to be a member of the same new gene family as
b
ARK,
sharing a similar tridomain structure.
27
Subsequently, we and others cloned additional members of this kinase
family such that today we know that there are seven members, referred
to as GRK1-7. Rhodopsin kinase is GRK1 and
b
ARK is GRK2. GRKs
2, 3, 5, and 6 are quite ubiquitously expressed, whereas GRK1 and 7 are
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