Signaling to the Nucleus by an L-type Calcium Channel-Calmodulin Complex Through the MAP Kinase Pathway

Increases in the intracellular concentration of calcium ([Ca2+]i) activate various signaling pathways that lead to the expression of genes that are essential for dendritic development, neuronal survival, and synaptic plasticity. The mode of Ca2+ entry into a neuron plays a key role in determining which signaling pathways are activated and thus specifies the cellular response to Ca2+. Ca2+ influx through L-type voltage-activated channels (LTCs) is particularly effective at activating transcription factors such as CREB and MEF-2. We developed a functional knock-in technique to investigate the features of LTCs that specifically couple them to the signaling pathways that regulate gene expression. We found that an isoleucine-glutamine (“IQ”) motif in the carboxyl terminus of the LTC that binds Ca2+-calmodulin (CaM) is critical for conveying the Ca2+ signal to the nucleus. Ca2+-CaM binding to the LTC was necessary for activation of the Ras/mitogen-activated protein kinase (MAPK) pathway, which conveys local Ca2+ signals from the mouth of the LTC to the nucleus. CaM functions as a local Ca2+ sensor at the mouth of the LTC that activates the MAPK pathway and leads to the stimulation of genes that are essential for neuronal survival and plasticity.

[1]  T. Snutch,et al.  Distinct calcium channels are generated by alternative splicing and are differentially expressed in the mammalian CNS , 1991, Neuron.

[2]  M E Greenberg,et al.  Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways. , 1993, Science.

[3]  Masatoshi Hagiwara,et al.  Phosphorylated CREB binds specifically to the nuclear protein CBP , 1993, Nature.

[4]  M E Greenberg,et al.  Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. , 1993, Science.

[5]  M. Greenberg,et al.  Serine 133-Phosphorylated CREB Induces Transcription via a Cooperative Mechanism That May Confer Specificity to Neurotrophin Signals , 1995, Molecular and Cellular Neuroscience.

[6]  R. Tsien,et al.  Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[7]  Michael E. Greenberg,et al.  Coupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB Kinase , 1996, Science.

[8]  K. Deisseroth,et al.  CREB Phosphorylation and Dephosphorylation: A Ca2+- and Stimulus Duration–Dependent Switch for Hippocampal Gene Expression , 1996, Cell.

[9]  M. Greenberg,et al.  Calcium Influx via the NMDA Receptor Induces Immediate Early Gene Transcription by a MAP Kinase/ERK-Dependent Mechanism , 1996, The Journal of Neuroscience.

[10]  Jiahuai Han,et al.  BMK1/ERK5 regulates serum‐induced early gene expression through transcription factor MEF2C , 1997, The EMBO journal.

[11]  Hilmar Bading,et al.  Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression , 1997, Nature.

[12]  A. Schwartz,et al.  Motif III S5 of L-type Calcium Channels Is Involved in the Dihydropyridine Binding Site , 1997, The Journal of Biological Chemistry.

[13]  K. Deisseroth,et al.  Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons , 1998, Nature.

[14]  M. Berridge.  Neuronal Calcium Signaling , 1998, Neuron.

[15]  T. Ishii,et al.  Mechanism of calcium gating in small-conductance calcium-activated potassium channels , 1998, Nature.

[16]  W. Catterall,et al.  Localization of Ca2+ Channel Subtypes on Rat Spinal Motor Neurons, Interneurons, and Nerve Terminals , 1998, The Journal of Neuroscience.

[17]  Scott T. Wong,et al.  Ca2+/calmodulin binds to and modulates P/Q-type calcium channels , 1999, Nature.

[18]  D. T. Yue,et al.  Calmodulin Is the Ca2+ Sensor for Ca2+-Dependent Inactivation of L-Type Calcium Channels , 1999, Neuron.

[19]  K. Deisseroth,et al.  Calmodulin supports both inactivation and facilitation of L-type calcium channels , 1999, Nature.

[20]  A. Shaywitz,et al.  CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. , 1999, Annual review of biochemistry.

[21]  E. Olson,et al.  MEF2: a transcriptional target for signaling pathways controlling skeletal muscle growth and differentiation. , 1999, Current opinion in cell biology.

[22]  M E Greenberg,et al.  Neuronal activity-dependent cell survival mediated by transcription factor MEF2. , 1999, Science.

[23]  R. Tsien,et al.  Ca2+-sensitive Inactivation and Facilitation of L-type Ca2+ Channels Both Depend on Specific Amino Acid Residues in a Consensus Calmodulin-binding Motif in theα1C subunit* , 2000, The Journal of Biological Chemistry.

[24]  W. Catterall.  Structure and regulation of voltage-gated Ca2+ channels. , 2000, Annual review of cell and developmental biology.

[25]  A. Means,et al.  Calmodulin: a prototypical calcium sensor. , 2000, Trends in cell biology.

[26]  D. T. Yue,et al.  Critical Determinants of Ca2+-Dependent Inactivation within an EF-Hand Motif of L-Type Ca2+ Channels , 2000 .

[27]  A. West,et al.  Calcium regulation of neuronal gene expression , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Hilmar Bading,et al.  Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity , 2001, Nature Neuroscience.

[29]  K. Deisseroth,et al.  Activity-dependent CREB phosphorylation: Convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Wilkin,et al.  Neuron , 2001, Brain Research.