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The web site itself may have changed. You can check the current page or check for previous versions at the Internet Archive. Yahoo! is not affiliated with the authors of this page or responsible for its content. Circadian Clock-Controlled Regulation of cGMPProtein Kinase G in the Nocturnal Domain Behavioral/Systems Circadian Clock-Controlled Regulation of cGMPProtein Kinase G in the Nocturnal Domain Shelley A. Tischkau, 1 E. Todd Weber, 2 Sabra M. Abbott, 2 Jennifer W. Mitchell, 1 and Martha U. Gillette 1,2 Departments of 1 Cell and Structural Biology and 2 Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 60801 The suprachiasmatic nucleus (SCN) circadian clock exhibits a recurrent series of dynamic cellular states, characterized by the ability of exogenous signals to activate defined kinases that alter clock time. To explore potential relationships between kinase activation by exogenous signals and endogenous control mechanisms, we examined clock-controlled protein kinase G (PKG) regulation in the mam- malian SCN. Signaling via the cGMPPKG pathway is required for light- or glutamate (GLU)-induced phase advance in late night. Spontaneous cGMPPKG activation occurred at the end of subjective night in free-running SCN in vitro. Phasing of the SCN rhythm in vitro was delayed by 3 hr after treatment with guanylyl cyclase (GC) inhibitors, PKG inhibition, or antisense oligodeoxynucleotide ( ODN) specific for PKG, but not PKA inhibitor or mismatched ODN. This sensitivity to GCPKG inhibition was limited to the same 2 hr time window demarcated by clock-controlled activation of cGMPPKG. Inhibition of the cGMPPKG pathway at this time caused delays in the phasing of four endogenous rhythms: wheel-running activity, neuronal activity, cGMP, and Per1. Timing of the cGMPPKG- necessary window in both rat and mouse depended on clock phase, established by the antecedent light/dark cycle rather than solar time. Because behavioral, neurophysiological, biochemical, and molecular rhythms showed the same temporal sensitivities and qualitative responses, we predict that clock-regulated GCcGMPPKG activation may provide a necessary cue as to clock state at the end of the nocturnal domain. Because sensitivity to phase advance by lightGLU-activated GCcGMPPKG occurs in juxtaposition, these signals may induce a premature shift to this PKG-necessary clock state.
Key words: protein kinase G (PKG); suprachiasmatic nucleus (SCN); circadian; Per1; cGMP; oligodeoxynucleotide (ODN) Introduction Circadian timekeeping, even in complex nervous systems, is a
property of cells (Michel et al., 1993; Welsh et al., 1995). Ordered,
clock-regulated changes in cellular processes partition clock
functions into a series of specific time domains that define time of
day (Gillette and Mitchell, 2002). The coordinated function of a
core group of clock genes and their protein products, articulated
by a highly conserved transcriptionaltranslational feedback
loop, provides a framework for molecular definitions of time
domains (Okamura et al., 2002). Regulation of clock elements is mediated by complex cellular processes, including post-translational modifications of proteins
via phosphorylation (Garceau et al., 1997; Merrow et al., 1997;
Kloss et al., 2001; Lee et al., 2001; Lin et al., 2001; Ripperger and
Schibler, 2001; Okamura et al., 2002). Hyperphosphorylation is
characteristic of the Drosophila clock elements, PERIOD (dPER) (Kloss et al., 2001) and TIMELESS (dTIM) (Price et al., 1995), as
well as the Neurospora clock protein, FREQUENCY (FRQ)
(Garceau et al., 1997), during restricted parts of their circadian
cycles and is accomplished by specific kinases. dPER is phosphor-
ylated and destabilized by DOUBLETIME (DBL). The effects of
light on Drosophila (Naidoo et al., 1999) and Neurospora (Yang et
al., 2001) clock elements are also phosphorylation-dependent. The type of molecular control of circadian timing exhibited by Drosophila and Neurospora is conserved in the mammalian clock
in the suprachiasmatic nucleus (SCN) (Okamura et al., 2002).
Transcripts of the mammalian homologs (Per1, Per2, Per3) of
dPer oscillate in the SCN (Albrecht et al., 1997; Shearman et al.,
1997; Shigeyoshi et al., 1997; Sun et al., 1997; Tei et al., 1997).
Transcription of mPer1 is induced by light at night, much like frq
(Crosthwaite et al., 1997), whereas the pattern of expression of
mPer2 is reminiscent of dPer (Zeng et al., 1994; Albrecht et al.,
1997; Okamura et al., 2002). Kinase-driven phosphorylation
events, whose mediators include casein kinase I and glycogen
synthase kinase orthologs of dDBL and dSHAGGY, respectively
(Kloss et al., 1998; Lowrey et al., 2000; Martinek et al., 2001), also
regulate putative mammalian clock elements. Additionally, cir-
cadian changes in the phosphorylation states of mPER1, mPER2,
CLOCK, and BMAL have been demonstrated (Lee et al., 2001). Complementing the molecular genetic studies, experimental manipulation of kinases alters rhythms in diverse circadian sys-
tems (Eskin et al., 1984; Prosser and Gillette, 1989; Prosser et al.,
1989; Liu and Gillette, 1996; Krucher et al., 1997; Liu et al., 1997; Received May 8, 2003; revised June 27, 2003; accepted July 2, 2003. This work was supported by National Institutes of Health (NIH) Grants NS22155, HL67007, and a University Scholar award (M.U.G.), NIH Grant NS10170 (S.A.T.), NIH Grant GM07143 (S.M.A.), and NIH Grant NS11158 (J.W.M.).
We thank U. Schibler for mPer1 probe and S. Baker for manuscript preparation. CorrespondenceshouldbeaddressedtoDr.M.U.Gillette,DepartmentofCellandStructuralBiology,Universityof Illinois at Urbana-Champaign, B107 Chemical and Life Sciences Laboratory, 601 South Goodwin Avenue, Urbana, IL
60801. E-mail: mgillett@life.uiuc.edu. S. A. Tischkaus present address: Department of Veterinary Biosciences, University of Illinois at Urbana- Champaign, 3615 VMBSB, 2001 South Lincoln Avenue, Urbana, IL 60801. E. T. Webers present address: Department of Biology, Rider University, 2083 Lawrenceville Road, Lawrenceville, NJ 08648.
Copyright
The web site itself may have changed. You can check the current page or check for previous versions at the Internet Archive. Yahoo! is not affiliated with the authors of this page or responsible for its content. Circadian Clock-Controlled Regulation of cGMPProtein Kinase G in the Nocturnal Domain Behavioral/Systems Circadian Clock-Controlled Regulation of cGMPProtein Kinase G in the Nocturnal Domain Shelley A. Tischkau, 1 E. Todd Weber, 2 Sabra M. Abbott, 2 Jennifer W. Mitchell, 1 and Martha U. Gillette 1,2 Departments of 1 Cell and Structural Biology and 2 Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 60801 The suprachiasmatic nucleus (SCN) circadian clock exhibits a recurrent series of dynamic cellular states, characterized by the ability of exogenous signals to activate defined kinases that alter clock time. To explore potential relationships between kinase activation by exogenous signals and endogenous control mechanisms, we examined clock-controlled protein kinase G (PKG) regulation in the mam- malian SCN. Signaling via the cGMPPKG pathway is required for light- or glutamate (GLU)-induced phase advance in late night. Spontaneous cGMPPKG activation occurred at the end of subjective night in free-running SCN in vitro. Phasing of the SCN rhythm in vitro was delayed by 3 hr after treatment with guanylyl cyclase (GC) inhibitors, PKG inhibition, or antisense oligodeoxynucleotide ( ODN) specific for PKG, but not PKA inhibitor or mismatched ODN. This sensitivity to GCPKG inhibition was limited to the same 2 hr time window demarcated by clock-controlled activation of cGMPPKG. Inhibition of the cGMPPKG pathway at this time caused delays in the phasing of four endogenous rhythms: wheel-running activity, neuronal activity, cGMP, and Per1. Timing of the cGMPPKG- necessary window in both rat and mouse depended on clock phase, established by the antecedent light/dark cycle rather than solar time. Because behavioral, neurophysiological, biochemical, and molecular rhythms showed the same temporal sensitivities and qualitative responses, we predict that clock-regulated GCcGMPPKG activation may provide a necessary cue as to clock state at the end of the nocturnal domain. Because sensitivity to phase advance by lightGLU-activated GCcGMPPKG occurs in juxtaposition, these signals may induce a premature shift to this PKG-necessary clock state.
Key words: protein kinase G (PKG); suprachiasmatic nucleus (SCN); circadian; Per1; cGMP; oligodeoxynucleotide (ODN) Introduction Circadian timekeeping, even in complex nervous systems, is a
property of cells (Michel et al., 1993; Welsh et al., 1995). Ordered,
clock-regulated changes in cellular processes partition clock
functions into a series of specific time domains that define time of
day (Gillette and Mitchell, 2002). The coordinated function of a
core group of clock genes and their protein products, articulated
by a highly conserved transcriptionaltranslational feedback
loop, provides a framework for molecular definitions of time
domains (Okamura et al., 2002). Regulation of clock elements is mediated by complex cellular processes, including post-translational modifications of proteins
via phosphorylation (Garceau et al., 1997; Merrow et al., 1997;
Kloss et al., 2001; Lee et al., 2001; Lin et al., 2001; Ripperger and
Schibler, 2001; Okamura et al., 2002). Hyperphosphorylation is
characteristic of the Drosophila clock elements, PERIOD (dPER) (Kloss et al., 2001) and TIMELESS (dTIM) (Price et al., 1995), as
well as the Neurospora clock protein, FREQUENCY (FRQ)
(Garceau et al., 1997), during restricted parts of their circadian
cycles and is accomplished by specific kinases. dPER is phosphor-
ylated and destabilized by DOUBLETIME (DBL). The effects of
light on Drosophila (Naidoo et al., 1999) and Neurospora (Yang et
al., 2001) clock elements are also phosphorylation-dependent. The type of molecular control of circadian timing exhibited by Drosophila and Neurospora is conserved in the mammalian clock
in the suprachiasmatic nucleus (SCN) (Okamura et al., 2002).
Transcripts of the mammalian homologs (Per1, Per2, Per3) of
dPer oscillate in the SCN (Albrecht et al., 1997; Shearman et al.,
1997; Shigeyoshi et al., 1997; Sun et al., 1997; Tei et al., 1997).
Transcription of mPer1 is induced by light at night, much like frq
(Crosthwaite et al., 1997), whereas the pattern of expression of
mPer2 is reminiscent of dPer (Zeng et al., 1994; Albrecht et al.,
1997; Okamura et al., 2002). Kinase-driven phosphorylation
events, whose mediators include casein kinase I and glycogen
synthase kinase orthologs of dDBL and dSHAGGY, respectively
(Kloss et al., 1998; Lowrey et al., 2000; Martinek et al., 2001), also
regulate putative mammalian clock elements. Additionally, cir-
cadian changes in the phosphorylation states of mPER1, mPER2,
CLOCK, and BMAL have been demonstrated (Lee et al., 2001). Complementing the molecular genetic studies, experimental manipulation of kinases alters rhythms in diverse circadian sys-
tems (Eskin et al., 1984; Prosser and Gillette, 1989; Prosser et al.,
1989; Liu and Gillette, 1996; Krucher et al., 1997; Liu et al., 1997; Received May 8, 2003; revised June 27, 2003; accepted July 2, 2003. This work was supported by National Institutes of Health (NIH) Grants NS22155, HL67007, and a University Scholar award (M.U.G.), NIH Grant NS10170 (S.A.T.), NIH Grant GM07143 (S.M.A.), and NIH Grant NS11158 (J.W.M.).
We thank U. Schibler for mPer1 probe and S. Baker for manuscript preparation. CorrespondenceshouldbeaddressedtoDr.M.U.Gillette,DepartmentofCellandStructuralBiology,Universityof Illinois at Urbana-Champaign, B107 Chemical and Life Sciences Laboratory, 601 South Goodwin Avenue, Urbana, IL
60801. E-mail: mgillett@life.uiuc.edu. S. A. Tischkaus present address: Department of Veterinary Biosciences, University of Illinois at Urbana- Champaign, 3615 VMBSB, 2001 South Lincoln Avenue, Urbana, IL 60801. E. T. Webers present address: Department of Biology, Rider University, 2083 Lawrenceville Road, Lawrenceville, NJ 08648.
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