Please wait while the transcript is being prepared...
0:00
Welcome, everyone,
to Chapter 14 of
this short talk series on
Nuclear Receptors as
Therapeutic Targets.
0:10
This chapter deals
with the retinoic acid
receptor-related
orphan receptors,
abbreviated as ROR,
which form the NR1F family
of nuclear receptors.
0:22
There are three ROR subtypes,
alpha, beta, and gamma,
which all act as
constitutively active
transcriptional activators.
As shown on the right,
the distribution of
the RORs varies substantially,
with ROR alpha and ROR gamma
being widely distributed
and ROR beta being only
expressed in a few organs,
including the brain.
The ROR subtypes and also
their splice variants differ
in the N-terminal domain,
and there are also
differences between
the subtypes in the
ligand-binding domains.
Although all RORs generally
respond to similar ligands,
these differences in the
ligand-binding domains
enable the development
of subtype-preferential
modulators
for at least some ROR subtypes.
Noteworthy is also
the splice variant or
ROR gamma t or ROR gamma 2,
in which the "t" stands for
thymocytes which is
found in immune cells.
However, the
ligand-binding domains of
ROR gamma 1 and t are identical,
and ligands likely have
the same effect on both.
1:28
We have seen in the
previous chapter that
RORs often act in
ensemble with revERBs.
Therein, RORs - constitutive
transcriptional activators,
and revERBs act as
the repressors.
Both receptor
families compete for
the same DNA response elements
and have opposing effects.
RORs are much better studied
in terms of ligands
than revERBs.
Based on the constitutive
activity of RORs,
ligands can act
mainly in two ways:
inverse agonists inhibit the
constitutive ROR activity;
and agonists enhance ROR
activity over the basal level.
You can see a selection
of ROR ligands.
Oxysterols are considered as
the natural ligands of
ROR alpha and gamma.
Therein, various
oxysterols are tolerated.
T0901317 and SR1078,
shown below the oxysterols,
are examples of early
synthetic ROR modulators.
They are not exceptionally
potent and not fully selective,
but have been very valuable
tools to study ROR biology.
Among RORs, the beta subtype
is least studied in terms
of ligands and seems to
bind somewhat different
ligand chemotypes.
All-trans retinoic acid,
other fatty acids,
and the fatty acid
mimetic ALRT1550
have been reported to
antagonize ROR beta activity,
but highly potent and
selective tools are lacking.
