Impaired Cerebellar Long-Term Potentiation in Type I Adenylyl Cyclase Mutant Mice

Studies carried out with mammals and invertebrates suggest that Ca(2+)-sensitive adenylyl cyclases may be important for neuroplasticity. Long-term potentiation in the hippocampus requires increases in intracellular Ca2+ which are accompanied by elevated cyclic AMP (cAMP). Furthermore, activation of cAMP-dependent protein kinase is required for the late stage of long-term potentiation in the CA1 region of the hippocampus, which is also sensitive to inhibitors of transcription. Therefore, some forms of synaptic plasticity may require coordinate regulation of transcription by Ca2+ and cAMP. In this study, we demonstrate that the expression of type I adenylyl cyclase in HEK-293 cells allows Ca2+ to stimulate reporter gene activity mediated through the cAMP response element. Furthermore, simultaneous activation by Ca2+ and isoproterenol caused synergistic stimulation of transcription in HEK-293 cells and cultured neurons. We propose that Ca2+ and neurotransmitter stimulation of type I adenylyl cyclase may play a role in synaptic plasticity by generating optimal cAMP signals for regulation of transcription.

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Type I adenylyl cyclase functions as a coincidence detector for control of cyclic AMP response element-mediated transcription: synergistic regulation of transcription by Ca2+ and isoproterenol.

Molecular and Cellular Biology ◽

10.1128/mcb.14.12.8272 ◽

1994 ◽

Vol 14 (12) ◽

pp. 8272-8281 ◽

Cited By ~ 49

Author(s):

S Impey ◽

G Wayman ◽

Z Wu ◽

D R Storm

Keyword(s):

Cyclic Amp ◽

Adenylyl Cyclase ◽

Long Term Potentiation ◽

Regulation Of Transcription ◽

Type I ◽

Hek 293 ◽

293 Cells ◽

Term Potentiation ◽

Stimulation Of

Studies carried out with mammals and invertebrates suggest that Ca(2+)-sensitive adenylyl cyclases may be important for neuroplasticity. Long-term potentiation in the hippocampus requires increases in intracellular Ca2+ which are accompanied by elevated cyclic AMP (cAMP). Furthermore, activation of cAMP-dependent protein kinase is required for the late stage of long-term potentiation in the CA1 region of the hippocampus, which is also sensitive to inhibitors of transcription. Therefore, some forms of synaptic plasticity may require coordinate regulation of transcription by Ca2+ and cAMP. In this study, we demonstrate that the expression of type I adenylyl cyclase in HEK-293 cells allows Ca2+ to stimulate reporter gene activity mediated through the cAMP response element. Furthermore, simultaneous activation by Ca2+ and isoproterenol caused synergistic stimulation of transcription in HEK-293 cells and cultured neurons. We propose that Ca2+ and neurotransmitter stimulation of type I adenylyl cyclase may play a role in synaptic plasticity by generating optimal cAMP signals for regulation of transcription.

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Transgenic Overexpression of the Type I Isoform of Neuregulin 1 Affects Working Memory and Hippocampal Oscillations but not Long-term Potentiation

Cerebral Cortex ◽

10.1093/cercor/bhr223 ◽

2011 ◽

Vol 22 (7) ◽

pp. 1520-1529 ◽

Cited By ~ 43

Author(s):

Inga H. Deakin ◽

Wiebke Nissen ◽

Amanda J. Law ◽

Tracy Lane ◽

Riam Kanso ◽

...

Keyword(s):

Working Memory ◽

Long Term Potentiation ◽

Type I ◽

Neuregulin 1 ◽

Term Potentiation

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Regulation of type I adenylyl cyclase by calmodulin kinase IV in vivo.

Molecular and Cellular Biology ◽

10.1128/mcb.16.11.6075 ◽

1996 ◽

Vol 16 (11) ◽

pp. 6075-6082 ◽

Cited By ~ 64

Author(s):

G A Wayman ◽

J Wei ◽

S Wong ◽

D R Storm

Keyword(s):

Adenylyl Cyclase ◽

Long Term Potentiation ◽

Type I ◽

Cam Kinase ◽

Regulatory Systems ◽

Calmodulin Kinase ◽

Term Potentiation ◽

G Protein Coupled ◽

Cam Kinase Iv

Type I adenylyl cyclase is a neurospecific enzyme that is stimulated by Ca2+ and calmodulin (CaM). This enzyme couples the Ca2+ and cyclic AMP (cAMP) regulatory systems in neurons, and it may play an important role for some forms of synaptic plasticity. Mutant mice lacking type I adenylyl cyclase show deficiencies in spatial memory and altered long-term potentiation (Z. Wu, S. A. Thomas, Z. Xia, E. C. Villacres, R. D. Palmiter, and D. R. Storm, Proc. Natl. Acad. Sci. USA 92:220-224, 1995). Although type I adenylyl cyclase is synergistically stimulated by Ca2+ and G-protein-coupled receptors in vivo, very little is known about mechanisms for inhibition of the enzyme. Here, we report that type I adenylyl cyclase is inhibited by CaM kinase IV in vivo. Expression of constitutively active or wild-type CaM kinase IV inhibited Ca2+ stimulation of adenylyl cyclase activity without affecting basal or forskolin-stimulated activity. Type I adenylyl cyclase has two CaM kinase IV consensus phosphorylation sequences near its CaM binding domain at Ser-545 and Ser-552. Conversion of either serine to alanine by mutagenesis abolished CaM kinase IV inhibition of adenylyl cyclase. This suggests that the activity of this enzyme may be directly inhibited by CaM kinase IV phosphorylation. Type VIII adenylyl cyclase, another enzyme stimulated by CaM, was not inhibited by CaM kinase II or IV. We propose that CaM kinase IV may function as a negative feedback regulator of type I adenylyl cyclase and that CaM kinases may regulate cAMP levels in some cells.

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Adenylyl cyclase-dependent form of chemical long-term potentiation triggers translational regulation at the elongation step

Neuroscience ◽

10.1016/s0306-4522(02)00797-2 ◽

2003 ◽

Vol 116 (3) ◽

pp. 743-752 ◽

Cited By ~ 50

Author(s):

J.K Chotiner ◽

H Khorasani ◽

A.C Nairn ◽

T.J O’Dell ◽

J.B Watson

Keyword(s):

Adenylyl Cyclase ◽

Translational Regulation ◽

Long Term Potentiation ◽

Term Potentiation ◽

Dependent Form ◽

Elongation Step

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Differential expression of long-term potentiation among identified inhibitory inputs to dopamine neurons

Journal of Neurophysiology ◽

10.1152/jn.00270.2017 ◽

2017 ◽

Vol 118 (4) ◽

pp. 1998-2008 ◽

Cited By ~ 6

Author(s):

DeNard V. Simmons ◽

Alyssa K. Petko ◽

Carlos A. Paladini

Keyword(s):

Nucleus Accumbens ◽

Adenylyl Cyclase ◽

Ventral Tegmental Area ◽

Cyclic Gmp ◽

Long Term Potentiation ◽

Dopamine Neurons ◽

Gaba Neurons ◽

Tegmental Nucleus ◽

Term Potentiation

The in vivo firing pattern of ventral tegmental area (VTA) dopamine neurons is controlled by GABA afferents originating primarily from the nucleus accumbens (NAc), rostromedial tegmental nucleus (RMTg), and local GABA neurons within the VTA. Although different forms of plasticity have been observed from GABA inputs to VTA dopamine neurons, one dependent on cyclic GMP synthesis and the other on adenylyl cyclase activation, it is unknown whether plasticity is differentially expressed in each. Using an optogenetic strategy, we show that identified inhibitory postsynaptic currents (IPSCs) from local VTA GABA neurons and NAc afferents exhibit a cyclic GMP-dependent long-term potentiation (LTP) that is capable of inhibiting the firing activity of dopamine neurons. However, this form of LTP was not induced from RMTg afferents. Only an adenylyl cyclase-mediated increase in IPSCs was exhibited by all three inputs. Thus discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons. NEW & NOTEWORTHY We describe a mapping of plasticity expression, mediated by different mechanisms, among three distinct GABA afferents to ventral tegmental area (VTA) dopamine neurons: the rostromedial tegmental nucleus, the nucleus accumbens, and the local GABA neurons within the VTA known to synapse on VTA dopamine neurons. This work is the first demonstration that discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons.

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