Essay: Ca2+ activates CaMKII

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Ca2+ activates CaMKII
Ca2+ is probably the most common second messenger in neurons and it can activate multiple intracellular signalling pathways (Ataei, Sabzghabaee, & Movahedian, 2015). Aside from release by the ER, calcium can enter the neuron from the extracellular medium via various Ca2+-permeable ion channels. These include voltage-gated Ca2+ channels and ligand-gated Ca2+ channels, both located at the plasma membrane. Normally the Ca2+ concentration in the cytosol is extremely low, 10-9 M, and the concentration outside the neurons is much higher, 10-3 M. Activation of these Ca2+ channels causes a large amount of Ca2+ to enter the postsynaptic cell. There are a few mechanisms for a neuron to maintain its intracellular Ca2+ concentration. Na+/Ca2+ exchangers and Ca2+ pumps are ion channels located at the plasma membrane that transport Ca2+ to the outer cell medium. In addition, Ca2+ is stored in the ER and mitochondria via Ca2+ pumps, so they can be released later for signalling events. Lastly, Ca2+ can bind reversibly to calbindin, which is a Ca2+-binding protein that serves as a Ca2+ buffer. These mechanisms for accurately elevate and descend Ca2+ concentrations give the cell the opportunity to precisely control signalling events. A sudden local rise of intracellular Ca2+ allows them to bind to various Ca2+-binding proteins for signalling events. One of them is calmodulin (CaM), which becomes activated after binding of four calcium ions (Ataei et al., 2015). The Ca2+/CaM complex is able to activate a Ca2+-dependent kinases. In neurons, the most abundant Ca2+/CaM-dependent kinase is Ca2+/calmodulin-dependent protein kinase type II (CaMKII). It makes up 1%-2% of the total brain proteins and in neurons it appears to be present twice as much in the spines as in the dendritic shafts (Hell, 2014). CaMKII is formed by twelve catalytically active subunits (figure 2).

Figure 2. CaMKII and its activation. (A) CaMKII consists of twelve subunits. Ca2+/CaM or phosphorylation of Thr286 can activate CaMKII in the regulatory segment, causing the kinase domains to extend from the hub domain. (B) The domains of one CaMKII subunit (Stratton et al., 2014).

There are four different subtypes, CaMKIIα-CaMKIIδ, with the subunits α and β most prevalent in the brain. In low Ca2+ conditions, the inhibitory domain covers the catalytic site, which can be referred to as an auto-inhibitory mechanism (Dupont, Houart, & De Koninck, 2003). When Ca2+ levels rise intracellularly, activation of CaMKII starts by binding of Ca2+/CaM to its regulatory domain, displacing the inhibitory domain from the catalytic domain. When Ca2+/CaM binds to two neighbouring subunits of CaMKII, autophosphorylation at T286 in CaMKIIα and at T287 CaMKIIβ can take place. Autophosphorylation of the twelve subunits makes the enzyme active, which then is able to function as a serine/threonine protein kinase with a large number of substrates (Hell, 2014).

Neurons organise their cytoplasm with multiple compartments and active transport. Different cargos, such as synaptic vesicle precursors, mitochondria and neurotransmitters move through the neuron via various molecular motor proteins, which can bind to the microtubule and actin cytoskeleton. Cargos are transported over long distances via motor proteins along microtubules. Then the cargos are taken over by actin filaments for their eventual destination. Motor proteins have fundamental roles in neuronal function, morphogenesis and survival via the transport of neurotransmitters and receptors (Hirokawa et al., 2010).

There are three classes of motor proteins; kinesins, dyneins and myosins. Kinesins and dyneins move along microtubules (figure 3) and myosins move along actin. In the axon and dendrites, transport occurs in two directions, anterograde and retrograde. Anterograde transport takes place from the cell body to the periphery, retrograde transport from the periphery to the cell body. Motor proteins recognise the polarity of the microtubule or actin filament and they will move unidirectional, anterograde or retrograde. Bidirectional transport is established differently in axons and dendrites (Hirokawa et al., 2010). In axons, kinesin superfamily proteins (KIFs) perform anterograde and dyneins retrograde transport. However, in dendrites anterograde and retrograde transport can be both achieved by kinesins. Myosins take care of the short range transport in growth cones and pre- and postsynapses, anterograde and retrograde. These motor proteins must recognise their cargos to bring it to their destination for proper cell function. Also a combination of filaments, different motors and regulatory proteins must work together to deliver the right cargo at the right time to the right place (Gross, Vershinin, & Shubeita, 2007). The components of axons and dendrites differ greatly. Therefore proteins must be distributed specifically. Transport specificity is believed to be achieved by binding of the cargo to motor proteins via adaptor or scaffolding proteins, which is essential for neuronal development and plasticity (Karcher, Deacon, & Gelfand, 2002). Adaptor proteins are believed to direct motor proteins into dendrites or axons, functioning as a sorting mechanism (Kennedy & Ehlers, 2006). Each motor binds its cargo differently, as will be elucidated below. The properties of the individual motor proteins, how they are distributed in the neuron and how they bind their cargo are investigated in order to understand how a cell can achieve these transport processes.

Kinesin superfamily
Mammals have 45 different kinesin superfamily proteins (KIFs), each having other characteristics. A kinesin motor generally consists of a motor domain that interacts with the microtubules, a stalk region and a tail domain. The stalk domain is generally used to dimerize with each other. Some KIFs however exist as monomers. KIFs associate with their cargos through their tail domains via light chains (KLC),

Figure 3. Microtubule-based motor transport. Kinesin motors consist of microtubule-binding kinesin heavy chain, a coiled coil for dimerization and a kinesin light chain for cargo binding. Dynein binds to dynactin and together they bind to microtubules. Kinesin moves towards the microtubule-plus-end and dynein towards the minus-end (Millecamps & Julien, 2013).
adaptor or scaffolding proteins (Hirokawa, Noda, Tanaka, & Niwa, 2009). By binding to adaptor or scaffolding proteins, the recognition and transport of cargos can be regulated. Therefore, it is important for a tail domain to be specific for these proteins. The kinesin motor domain, identified as the globular heavy chain (KHC), has a adenosine triphosphate (ATP)-binding sequence and a microtubule-binding sequence. ATP functions as fuel to generate plus-ended stepping-like behaviour by the two motor domains. Hydrolysing ATP generates the force to move along the microtubules. The velocities of the different KIFs vary from 0.1 µm s-1 to 1.5 µm s-1 (Hirokawa et al., 2009; Hirokawa & Takemura, 2005). Some KIFs can regulate their own activity by autoinhibition (Hirokawa et al., 2010; Schlager & Hoogenraad, 2009). When cargos aren’t bound to the motor protein, the tail domains associates with the motor domains in the same molecule in order to inhibit its activity.

KIFs consist of three major groups based on the positions of their motor domains (Hirokawa et al., 2010). N-KIFs have their motor domain at the NH2-terminal, M-KIFs in the middle and C-KIFs at the COOH-terminal of the molecule. The direction of the kinesin is determined by the position of the motor domain. N-KIFs generally are directed to the plus end of the microtubule, whereas C-KIFs deliver minus end directed transport. M-KIFs also move towards the plus end of the microtubule, but have a microtubule-depolymerizing activity. Each of these three classes can be further classified. N-KIFs contain eleven classes, amongst others KIF1, KIF3, KIF4, KIF5, KIF13 and KIF17. C-KIFs include two classes, KIFC1 and KIFC2/C3. M-KIFs only consist of one class, KIF2. The shapes of each of these KIFs vary, resulting in different cargo binding and different destinations to reach.

In axons, different membranous organelles are transported from the cell body to the synaptic terminals (figure 4a). These include the following. Monomers KIF1A and KIF1Bβ transport synaptic vesicle precursors through the adaptor protein mitogen-activated protein kinase-activating death domain (DENN/MADD). KIF3 transports vesicles with fodrin (Fod). Mitochondria are transported anterograde via KIF5 and KIF1Bα. The latter is via the adaptor protein KIF1Bα-binding protein (KBP) localized to mitochondria, whereas KIF5 is attached to them via the adaptor proteins syntabulin, Ran-binding protein 2 (RanBP2) and the Milton-Miro complex. KIF5 also transports via its KLC vesicles containing amyloid precursor protein (APP), which is the precursor protein of amyloid-β that is deposited in the brains of Alzheimer’s disease patients. In addition, KIF5 is bound to vesicles with the apolipoprotein E receptor 2 (ApoER2) through its KLC. The growth of axon collaterals in growth cones is supressed by KIF2A through its depolymerizing activity of microtubules.

The polarity of the microtubules is mixed in the proximal dendrites, but they become unipolar at the more distal regions with their plus ends pointed away from the cell body. In dendrites, chemical transmitter receptors and mRNAs are mainly transported from the cell body to the synaptic regions (figure 4a). These include the NMDAR and AMPAR, which are activated by the release of glutamate in the synaptic cleft. Vesicles containing the NMDAR are transported by KIF17. The subunit NR2B of the NMDAR can bind to the scaffolding complex mLin-7 (MALS) and mLin-2 (CASK), and via this complex it binds to mLin-10 (Mint1), which binds directly to KIF17 (figure 4b) (Hirokawa & Noda, 2008). KIF17 is believed to contribute to neuronal events important for learning and memory by trafficking these receptors towards spines. Microtubule bundles at the initial segment, which lay at the proximal part of the axon near the cell body, may function as cue for axonal transport for KIF5 (Hirokawa et al., 2009; Hirokawa & Takemura, 2004). However, KIF5 also transports vesicles with the AMPAR in dendrites. The motor-cargo binding domain of KIF5 binds to the adaptor protein glutamate receptor-interacting protein (GRIP1), which then binds to the GluR2 subunit of AMPARs (figure 4b). Finally, the motor KIFC2 transports multivesicular body-like vesicles (MVB) from the most distal regions of the dendrites towards the minus end of the microtubule.

Figure 4. Cargo transport by KIFs. (a) In axons, the microtubule polarity is unipolar with its anterograde plus-end. Their polarity is mixed in dendrites. Most KIFs move towards the plus-ends, with KIFC2 as an exception. MBV: multivesicular body-like vesicle, AMPAR: AMPA receptor, NMDAR: NMDA receptor, APP: amyloid precursor protein, Mito: mitochondrion, ApoER2: apolipoprotein E receptor 2, Fod: fodrin, SV: synaptic vesicle. (b) KIF17 transports NR2B containing vesicles via the adaptor complex MALS/CASK/Mint1. GluR2-containing vesicles are transported by KIF5 via the GRIP1 (Hirokawa & Takemura, 2004).

Dynein superfamily
Together with C-KIFs, dynein provides minus ended transport along microtubules and hydrolyse ATP to generate force and movement (figure 3). Dyneins can be sorted into two groups, cytoplasmic and axonemal, which is ciliary or flagellar. The retrograde motor is composed of two heavy chains, two intermediate chains and several light chains. The heavy chains have ATP-binding domains that create movement along microtubules (Hirokawa et al., 2010). Cytoplasmic dynein is allied with the protein complex dynactin, which regulates the activity of dynein and the binding to its cargos. In contrast to kinesins, which use their own tail regions for cargo recognition, cytoplasmic dyneins recognise their cargo through direct binding or altering of the intermediate and light chains of the dynein or dynactin complex to the cargo. Therefore, they can acquire various cargo associations.

Myosin superfamily
Myosins are motor proteins that contain a motor domain, neck and tail region and most of them form dimers. With their motor domains they move along the actin network in presynaptic terminals and postsynaptic spines by hydrolysing ATP. In the ADP-bound state, kinesins bind weakly to microtubules, whereas myosins bind strongly to actin filaments (Hirokawa & Noda, 2008). Next to translocating postsynaptic organelles and proteins, myosins may take over the cargo transport to the more distal regions of dendrites and axons after the long distance transport via the microtubule-KIF system. Myosins can be classified into 18 classes. In neurons, the myosin superfamily proteins myosin Va, myosin Vb and myosin VI are primarily involved pre- and postsynaptic transport. Myosin II contributes in muscle cells and in the migration of neurons and in growth cones. It also plays an important role in synaptic plasticity by giving mechanical force on the actin cytoskeletons and thus modulating spine shape. The movement of myosin VI is towards the pointed, minus end of F-actin and is involved in internalization and the retrograde transport of AMPAR-containing vesicles. Via the protein SAP97, which is related to PSD-95, it binds to the GluR1 subunit of AMPARs. Myosin Va and Vb, which are homologous resembling to each other, are processive proteins which makes them good motors for translocating organelles efficiently (Hammer & Wagner, 2013).

Myosin Va moves to the postsynaptic densities in dendrites, transporting the AMPAR subunit GluR1, and to vesicle fractions in axons, where it transports ER-vesicles. In spines, myosin Va binds with its globular tail domains to guanylate kinase-associated protein GKAP, which interacts with PSD-95. This is important for anchoring glutamate receptors at the postsynaptic membrane. Myosin Vb also moves towards the barbed, plus end of F-actin and transports recycling endosomes containing AMPARs and triggers their exocytosis in dendritic spines when activated (Hirokawa et al., 2010). Myosin Vb is a homodimer with each monomer consisting of an N-terminal motor domain, a neck region that binds to CaM, and a tail region. The tail region consists of a coiled-coil region, which provides dimerization, and a globular tail that can associate with cargo. Myosin Vb can recognize its cargo via the Rab11-FIP complex, consisting of a RE-specific Rab GTPase Rab11 and its effector Rab11-FIP2, which are present on the surface of recycling endosomes (figure 5).

Multiple different motors have been identified to be bound to a single cargo. Kinesins, dyneins and myosins are stably attached to some cargos, so that the cargo will not fall of the filaments easily and will not diffuse before it reaches its destination (Welte, 2004). Besides, two cargo-bound motors that move in the same direction will bring the cargo much further than a single motor (Gross et al., 2007). The regulating factor for bidirectional movement is now not only established by the motor-cargo interaction. The length of the travel, the direction and motion can be correctly tuned by regulating the motor activity of the other motors present. Moreover, myosin Va interacts with kinesin and dynein, indicating that transport of postsynaptic cargo between the dendritic shafts and spines could be coordinated by myosin Va.

Figure 5. Schematic figures of myosin Vb and its domains. (a) Secondary structure of myosin Vb. Brackets indicate regions of myosin Vb that interact with other proteins. CaM: calmodulin. The numbers indicate amino acids. (b) Myosin Vb transports recycling vesicles along actin filaments. Myosin Vb is associated with REs via Rab11/Rab11-FIP2 (Z. Wang et al., 2008).

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