Plc

DAG release

PKC activation, pre and post

"Induction" mechanisms refer to the many processes reviewed in Chapter 6.

"Induction" mechanisms refer to the many processes reviewed in Chapter 6.

these have by far been the most extensively studied in the context of E-LTP.

Interestingly, CaM and the calcium-binding isoforms of PKC are the prototype molecules for the two major categories of calcium-binding proteins (see Figure 2). Each of these molecules has calcium-binding domains in their structure that define whole families of calcium-binding proteins. CaM is the prototype molecule for the "E-F hand" family of calcium-binding proteins. The E-F hand terminology derives from esoteric naming of the calcium-binding domain based on a lettered alpha-helix nomenclature (the E-F part), coupled with the fact that the domain could be modeled to look like a human hand in a specific configuration. (OK, since you asked, the hand configuration is the classic "six-shooter" configuration that boys use when they want to pretend to shoot each other). As a first approximation, you can think of the E-F hand structure as the generic calcium binding domain in proteins. A wide variety

FIGURE 2 Structures of calcium-binding proteins. (A) This panel gives three views of calcium (red spheres) bound to calmodulin, illustrating the structure of the E-F-hand subtype of calcium-binding protein. The first rendering shows the peptide backbone of calmodulin in dark blue. The second rendering is identical to the first except that the calmodulin structure is illustrated in space-filling spheres. The third rendering is identical to the second except that amino acids are rendered in the CPK convention (red = oxygen, blue = nitrogen, gray = carbon, yellow = sulfur). (B) This panel illustrates the interaction of Ca/calmodulin with a target effector. An alpha-helical domain of CaMKII is illustrated in light green to the right of the calmodulin molecule. As part of achieving its effects on target effectors calmodulin changes the structure of its own interdomain alpha helix, wrapping itself around the target. (C and D) Illustrations of the "C2 domain" subtype of calcium binding domain. These figures illustrate two different conformations of this type of calcium-binding domain, typified by the C2 domain of PKC alpha. (D) Structural changes induced by calcium (shown as red spheres) binding to the calcium-binding domain and adjacent regions of the molecule typically cause allosteric changes, promoting binding to phospholipid membranes. Structures based on data in Verdaguer et al. (124).

FIGURE 2 Structures of calcium-binding proteins. (A) This panel gives three views of calcium (red spheres) bound to calmodulin, illustrating the structure of the E-F-hand subtype of calcium-binding protein. The first rendering shows the peptide backbone of calmodulin in dark blue. The second rendering is identical to the first except that the calmodulin structure is illustrated in space-filling spheres. The third rendering is identical to the second except that amino acids are rendered in the CPK convention (red = oxygen, blue = nitrogen, gray = carbon, yellow = sulfur). (B) This panel illustrates the interaction of Ca/calmodulin with a target effector. An alpha-helical domain of CaMKII is illustrated in light green to the right of the calmodulin molecule. As part of achieving its effects on target effectors calmodulin changes the structure of its own interdomain alpha helix, wrapping itself around the target. (C and D) Illustrations of the "C2 domain" subtype of calcium binding domain. These figures illustrate two different conformations of this type of calcium-binding domain, typified by the C2 domain of PKC alpha. (D) Structural changes induced by calcium (shown as red spheres) binding to the calcium-binding domain and adjacent regions of the molecule typically cause allosteric changes, promoting binding to phospholipid membranes. Structures based on data in Verdaguer et al. (124).

of proteins, including CaM, troponin C, the S100s, and the calcium-binding subunits of the protease calpain and protein phosphatase 2B all contain E-F hand calcium-binding domains.

PKC is the prototype for the "C2 domain" family of calcium-binding proteins. As we will discuss later, the PKC superfamily is a heterogeneous group of proteins with variable (V) and conserved (C) domains. The second conserved domain (C2) is a calcium-binding domain. The C2 domain family of calcium-binding proteins typically bind both calcium and phospholipids, and calcium regulation of protein-membrane interactions is typical of this group (see Figure 2). Specific examples of C2 domain-containing proteins include the PKCs, the synaptic vesicle-associated protein synaptotagmin, and various phospholipases.

A. CaMKII in E-LTP

Calmodulin'Sensitive Enzymes

Calmodulin in the absence of calcium (apo-calmodulin) has a dumbbell-shaped structure with four E-F-hand calcium-binding domains (see Figure 2). Upon binding of calcium, which is a cooperative interaction, CaM undergoes an extensive conforma-tional change in which the "handle" part of the dumbbell twists itself around a target molecule alpha helix (see Figure 2). This calcium-dependent interaction leads to a conformational change in the target and typically triggers enzyme activation.

One of the most widely studied and important targets of CaM are the calcium/ calmodulin-dependent protein kinases (the CaMKs). There are two CaMK isoforms of particular significance in neurons:

Autophosphorylation Camkii

FIGURE 3 Structure of CaMKII. (A) Line diagram illustrating the catalytic, autoinhibitory, and association domains of CaMKII, as well as two sites of autophosphorylation. Reproduced from Lisman, Schulman, and Cline (6). Panels B and C illustrate a detailed and realistic model of CaMKII based on sophisticated high-resolution electron microscopy and X-ray diffraction techniques. (B) A top-down view of CaMKII showing 6 of the 12 individual subunits comprising the holoenzyme. Adapted from Lisman, Schulman, and Cline (6). (C) A stereo rendering of a side view of the same structure. This model shows that the core comprises an aggregate of 12 association domains (residues 315-478) and that the 12 "foot" regions extending from the core are the functional domains (residues 1-314). The ATP- and calmodulin-binding sites are near the middle of the foot (as indicated by the shaded region on one foot in Panel B). Reproduced from Kolodziej, Hudmon, Waxham, and Stoops (125).

FIGURE 3 Structure of CaMKII. (A) Line diagram illustrating the catalytic, autoinhibitory, and association domains of CaMKII, as well as two sites of autophosphorylation. Reproduced from Lisman, Schulman, and Cline (6). Panels B and C illustrate a detailed and realistic model of CaMKII based on sophisticated high-resolution electron microscopy and X-ray diffraction techniques. (B) A top-down view of CaMKII showing 6 of the 12 individual subunits comprising the holoenzyme. Adapted from Lisman, Schulman, and Cline (6). (C) A stereo rendering of a side view of the same structure. This model shows that the core comprises an aggregate of 12 association domains (residues 315-478) and that the 12 "foot" regions extending from the core are the functional domains (residues 1-314). The ATP- and calmodulin-binding sites are near the middle of the foot (as indicated by the shaded region on one foot in Panel B). Reproduced from Kolodziej, Hudmon, Waxham, and Stoops (125).

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Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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