Protein Kinases Dendrite Geometry and Synapse Formation

Principally, the intracellular signaling networks, which were discussed above in light of axon growth and arborization, also account for dendrite growth and arborization. There are, however, some exceptions to be made. For example, semaphorin 3A signaling exerts opposite effects with respect to axon and dendrite growth, respectively. How can this difference with respect to semaphorin 3A signaling be explained? As shown in Figure 21.2, semaphorin 3A activates RhoA and inhibits Rac pathways, respectively, thereby negatively modulating axon growth and providing a 'STOP' signal at the axon termination zone. Regarding dendrite growth, semaphorin 3A additionally engages other signaling pathways, which serve to convert repulsive into attractive cues. For example, Ghosh and colleagues found that the relative availability of guanylyl cyclase and in consequence of cyclic guanosine monophosphate (cGMP), and further downstream of serine/ threonine protein kinase G (PKG), might be critical for the conversion of repulsive into attractive semaphorin 3A cues28,29. In addition to this, nerve growth factor (NGF) binding to TrkA and concomitant MAPK activation was reported to counteract repulsive semaphorin 3-associated cues30; for advanced reading consult31.

As for axonal growth cones, the outgrowth of dendritic filopodia is positively modulated by PKC phosphorylation of MAPs. PKC activation can result from arachidonic acid liberation as a consequence of integrin-mediated cell adhesion and phospholipase A2 (PLA2) processing of membrane precursors32. The intracellular signal cascade implicated in the activation of PKC by arachidonic acid involves the generation of second messengers upon lipoxygenase-catalyzed oxidation of arachidonic acid, which are processed further downstream by PLC to DAG33. This recent discovery showed that astrocytes participate in the processes underlying synapse formation, and it is consistent with the requirement of the PKC-e isoform for arachidonic acid to translocate to the plasma membrane34. Thus, local integrin-mediated contact of astrocytes with neurons leads to a global enhancement of PKC activity, which in turn promotes neuronal differentiation including dendrite arborization and synapse formation.

In line with this, an increasing body of evidence identifies intracellular Ca2+ fluctuations as a major regulatory element in the control of dendrite arborization and growth. Indeed, almost a decade ago, the role of voltage-activated Ca2+ channels (VACC) and Ca2+-induced Ca2+ release was already realized35. Increasing intracellular Ca2+ levels provides a direct link to the activation of CaMK and furthermore to the translocation of classical PKC isoforms to the plasma membrane, where they exert their function. CaMKIIP activation stimulates the formation of glutamatergic synapses and, in addition, enhances dendrite complexity36. This effect is preferentially associated with CaMKIIP, and not with CaMKIIa, because CaMKIIP possesses an additional actin-binding sequence, which allows binding polymerized actin and regulation of actin polymerization36. However, Ca2+/calmodulin binding to CaMKIIP leads to a dissociation of the kinase from actin filaments, which is consistent with the idea that glutamatergic synaptic activity stabilizes dendritic branches and synapses by reducing actin-related cytoskeletal dynamics37.

CaMKIIa behaves in the opposite way, that is synaptic activity and concomitant Ca2+/calmodulin activation of CaMKIIa promotes association with a-actinin, which localizes the kinase to postsynaptic glutamatergic sites where it regulates the trafficking and stabilization of a-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) and A-methyl-D-aspartate receptors (NMDARs) at postsynaptic domains (Section 4.1)38. These considerations emphasize the fact that physiological conditions determine the functional output of kinases by tightly and dynamically regulating the balance between active and inactive kinases, and by the recruiting distinct active kinase isoforms to confined enzymatic compartments where phosphorylation of target proteins is required for appropriate neuron physiology.

To engross these thoughts, it should be considered here that glutamatergic synaptic transmission per se, which provides local sources for intracellular Ca2+ oscillations, was identified as a potent regulatory element with respect to dendrite growth, arborization, and synapse formation39. In fact, it is the Ca2+ permeability of NMDARs, which is a critical determinant in the development of dendritic arbors40. Interestingly, the Ca2+ permeability of NMDARs can even be increased in response to binding of the extracellular EphB2 domain. As a consequence of this, the GDP-GTP exchange factors kalirin and tiam are activated, which leads to activation of the Rac pathway (see Section 3.1, Figure 21.2). Another modulator of intracellular Ca2+ levels is the neurotrophin BDNF, which uses several pathways including the Src-family 59 kDa nonreceptor tyrosine kinase Fyn and PLCy. For example,

BDNF enhances excitatory postsynaptic currents through phosphorylation-dependent mechanisms and this involves an interaction through Fyn between the full-length high affinity neurotrophin receptor tyrosine kinase TrkB and the NMDAR 2B subunit41, whereby the TrkB-mediated tyrosine phosphorylation of the NMDAR increases the channel open probability42. Besides this, TrkB receptor activation provokes a depolarizing cation current through the transient receptor potential channel 3 (TrpC3), which consequently increases intracellular Ca2+ levels by VACC activation43.

An ever-growing number of kinases are associated with regulation of synapse formation, and to assemble some more pieces of the kinase - synaptogenesis puzzle, we also have to consider the modulatory effects PKA, MAPK, TrkB, and EphB exert on synapse formation (summarized in Table 1)44-48. However, rather than giving a detailed overview of the attributions of experimental manipulations of kinase activities and their effects on synapse numbers, I would like to discuss now some selected molecular signaling events situated between the experimental trigger and the determined synapse numbers, which orchestrate the results of protein phosphorylation up to the formation of new synapses.

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