Many distinct signaling pathways allow the cell to receive, process, and respond to information. Often, components of different pathways interact, resulting in signaling networks. Biochemical signaling networks were constructed with experimentally obtained constants and analyzed by computational methods to understand their role in complex biological processes. These networks exhibit emergent properties such as integration of signals across multiple time scales, generation of distinct outputs depending on input strength and duration, and self-sustaining feedback loops. Feedback can result in bistable behavior with discrete steady-state activities, well-defined input thresholds for transition between states and prolonged signal output, and signal modulation in response to transient stimuli. These properties of signaling networks raise the possibility that information for "learned behavior" of biological systems may be stored within intracellular biochemical reactions that comprise signaling pathways.

https://science.sciencemag.org/content/sci/283/5400/381.full.pdf

Emergent Properties of Networks of Biological Signaling Pathways

As a first step in a program to use genetically altered mice in the study of memory mechanisms, mutant mice were produced that do not express the alpha-calcium-calmodulin-dependent kinase II (alpha-CaMKII). The alpha-CaMKII is highly enriched in postsynaptic densities of hippocampus and neocortex and may be involved in the regulation of long-term potentiation (LTP). Such mutant mice exhibited mostly normal behaviors and presented no obvious neuroanatomical defects. Whole cell recordings reveal that postsynaptic mechanisms, including N-methyl-D-aspartate (NMDA) receptor function, are intact. Despite normal postsynaptic mechanisms, these mice are deficient in their ability to produce LTP and are therefore a suitable model for studying the relation between LTP and learning processes.

https://science.sciencemag.org/content/sci/257/5067/201.full.pdf

Deficient Hippocampal Long-Term Potentiation in α-Calcium-Calmodulin Kinase II Mutant Mice

The mechanism by which Ca2+ mediates gene induction in response to membrane depolarization was investigated. The adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB) was shown to function as a Ca(2+)-regulated transcription factor and as a substrate for depolarization-activated Ca(2+)-calmodulin-dependent protein kinases (CaM kinases) I and II. CREB residue Ser133 was the major site of phosphorylation by the CaM kinases in vitro and of phosphorylation after membrane depolarization in vivo. Mutation of Ser133 impaired the ability of CREB to respond to Ca2+. These results suggest that CaM kinases may transduce electrical signals to the nucleus and that CREB functions to integrate Ca2+ and cAMP signals.

https://science.sciencemag.org/content/sci/252/5011/1427.full.pdf

CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases

Neuronal activity can lead to marked increases in the concentration of cytosolic calcium, which then functions as a second messenger that mediates a wide range of cellular responses. Calcium binds to calmodulin and stimulates the activity of a variety of enzymes, including calcium-calmodulin kinases and calcium-sensitive adenylate cyclases. These enzymes transduce the calcium signal and effect short-term biological responses, such as the modification of synaptic proteins and long-lasting neuronal responses that require changes in gene expression. Recent studies of calcium signal-transduction mechanisms have revealed that, depending on the route of entry into a neuron, calcium differentially affects processes that are central to the development and plasticity of the nervous system, including activity-dependent cell survival, modulation of synaptic strength, and calcium-mediated cell death.

https://science.sciencemag.org/content/sci/268/5208/239.full.pdf

Calcium signaling in neurons: molecular mechanisms and cellular consequences

The dystrophin-glycoprotein complex was tested for interaction with several components of the extracellular matrix as well as actin. The 156-kD dystrophin-associated glycoprotein (156-kD dystroglycan) specifically bound laminin in a calcium-dependent manner and was inhibited by NaCl (IC50 = 250 mM) but was not affected by 1,000-fold (wt/wt) excesses of lactose, IKVAV, or YIGSR peptides. Laminin binding was inhibited by heparin (IC50 = 100 micrograms/ml), suggesting that one of the heparin-binding domains of laminin is involved in binding dystroglycan while negatively charged oligosaccharide moieties on dystroglycan were found to be necessary for its laminin-binding activity. No interaction between any component of the dystrophin-glycoprotein complex and fibronectin, collagen I, collagen IV, entactin, or heparan sulfate proteoglycan was detected by 125I-protein overlay and/or extracellular matrix protein-Sepharose precipitation. In addition, laminin-Sepharose quantitatively precipitated purified dystrophin-glycoprotein complex, demonstrating that the laminin-binding site is accessible when dystroglycan is associated with the complex. Dystroglycan of nonmuscle tissues also bound laminin. However, the other proteins of the striated muscle dystrophin-glycoprotein complex appear to be absent, antigenically dissimilar or less tightly associated with dystroglycan in nonmuscle tissues. Finally, we show that the dystrophin-glycoprotein complex cosediments with F-actin but does not bind calcium or calmodulin. Our results support a role for the striated muscle dystrophin-glycoprotein complex in linking the actin-based cytoskeleton with the extracellular matrix. Furthermore, our results suggest that dystrophin and dystroglycan may play substantially different functional roles in nonmuscle tissues.

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A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin

Publisher Summary This chapter discusses the presently known calcium (Ca 2+ )/calmodulin (CaM)-dependent protein kinases and some of their properties. To date, CaM kinase II is the only Ca 2+ )/CaM-dependent protein kinase known to phosphorylate a wide range of proteins and for this reason, it is sometimes referred to as the CaM-dependent multifunctional protein kinase or CaM-dependent multiprotein kinase. These properties, mainly established in vitro , together with the wide distribution of the kinase, suggest that CaM kinase II may be involved in the regulation of numerous physiological functions. The chapter summarizes the present knowledge of CaM kinase II with the particular emphasis on the molecular mechanisms involved in the regulation of kinase activity. It also reviews the literature concerning the putative physiological functions of the kinase. There is a great deal known about the in vitro properties of calmodulin (CaM) kinase II, both in terms of its substrate specificity and its regulation by CaM and autophosphorylation. Much of this characterization is based on the experiments performed with rat brain isozyme of CaM kinase II, although in the aspects examined to date isozymes of the kinase from other tissues appear to behave in a broadly similar manner in vitro . However, relatively little is known about the functions of the kinase in vivo . Investigation of the physiological role of the kinase in brain and other tissues will be a particularly exciting area for future work. The current knowledge of the in vitro properties and the availability of complimentary DNA (cDNA) clones will hopefully expedite this research.

/pdf/calcium-calmodulin-dependent-protein-kinase-ii-qswsppegf5.pdf

Calcium/calmodulin-dependent protein kinase II.

Reversible generation of a Ca2+-independent form of Ca2+(calmodulin)-dependent protein kinase II by an autophosphorylation mechanism.

Ca2+/calmodulin-dependent protein kinase II. Identification of a regulatory autophosphorylation site adjacent to the inhibitory and calmodulin-binding domains

https://www.jbc.org/content/262/17/8051.full.pdf

C. M. Schworer

Papers

Calcium/calmodulin-dependent protein kinase II.

Reversible generation of a Ca2+-independent form of Ca2+(calmodulin)-dependent protein kinase II by an autophosphorylation mechanism.

Ca2+/calmodulin-dependent protein kinase II. Identification of a regulatory autophosphorylation site adjacent to the inhibitory and calmodulin-binding domains

Autophosphorylation of Ca2+/calmodulin-dependent protein kinase II. Effects on total and Ca2+-independent activities and kinetic parameters.

Regulatory interactions of the calmodulin-binding, inhibitory, and autophosphorylation domains of Ca2+/calmodulin-dependent protein kinase II.