Protein Kinases and Pain Sensitization

16 May

Nearly 50 years ago, protein  phosphorylation was identified as a regulatory mechanism  for the control of glycogen metabolism. It took many years be- fore its general significance came to be appreciated.  Protein kinases almost regulate every aspect of cell life from growth to death. They mediate  most of the signal transduction in eukaryotic cells by regulating substrate activity via phosphorylation. Protein kinases are among the largest families of genes and have been intensively studied. The human genome encodes 518 protein kinases, accounting for 1.7% of all human genes (Manning et al. 2002). These kinases share a catalytic domain  conserved in sequence and structure  but also notably different in how their  catalysis is regulated.  The ATP binding pocket together with less-conserved surrounding pockets has been the focus of inhibitor design. Multiple protein kinases have been implicated in pain sen- sitization (Table 1). Importantly,  inhibitors  of protein  kinases do not affect physiological pain: the normal pain threshold  in response to mechanical or thermal  stimulus remains  unchanged.  The serine-threonine kinases consist of most protein  kinases, and many of serine-threonine kinases are involved in pain regulation (Table 1). There are also 90 tyrosine kinases in the human

Table 1 A list of protein kinases that are known to be involved in inflammatory  pain (IP), neuropathic  pain (NP), peripheral  sensitization  (PS), and central sensitization  (CS). See Sects. 2.1–2.3 for more details

Protein Kinases and Pain Sensitization

genome including receptor tyrosine kinases and nonreceptor tyrosine kinases (Manning et al. 2002); several tyrosine kinases are implicated in pain facil- itation. In particular,  we will discuss the roles of mitogen-activated  protein kinases (MAPKs) in regulating pathological pain (see Sect. 2.3), because there is increasing evidence suggesting that this family of serine/threonine kinases is critical for the induction  and maintenance  of pain hypersensitivity  after injuries (Ji and Woolf 2001).

Serine-Threonine Protein Kinases

Protein Kinase A (PKA)   This is one of the most classic kinases. Although protein kinase A (PKA) is typically activated by cyclic AMP (cAMP), cAMP’s actions are not exclusively mediated  by PKA. cAMP could activate Epac, a guanine nucleotide exchange factor, leading to the activation of p44/42 MAPK and the

ε-isoform of PKC. PKA has been strongly implicated in peripheral and central sensitization. The adenyl cyclase–cAMP–PKA pathway mediates sensitization

of the peripheral terminals of nociceptors induced by PGE2, a major inflam- matory mediator (Aley and Levine 1999). PKA is also required for the second phase nociceptive response to formalin and capsaicin-produced mechanical allodynia, two pain models that are thought to result from central sensitization (Coderre and Yashpal 1994; Sluka and Willis 1997). PKA also contributes  to the sensitization of spinal-thalamic  projection neurons in the lamina I of the

spinal cord following tissue injury (Willis 2002). These NK-1-expressing pro- jection neurons are essential for injury-induced  pain hypersensitivity (Man- tyh et al. 1997). In mice with a null mutation of the neuronal-specific isoform

of PKA’s type I regulatory  subunit  (RIβ), a selective deficit is found in the development  of inflammation  and  tissue injury-produced pain  (Malmberg et al. 1997a).

Protein Kinase C  PKC is activated by diacylglycerol (DAG) and Ca2+. There is substantial  evidence supporting  a role of spinal PKC in regulating pain hy- persensitivity in different pain models (Mao et al. 1992; Coderre 1992; Sluka and Willis 1997). PKC is also required for the sensitization of spinal-thalamic projection neurons in the lamina I following intense C fiber stimulation (Willis

2002). There is an increase in spinal cord membrane-bound PKC following nerve injury  (Mao et al. 1992). In particular,  the γ-isoform of PKC is ex- pressed predominantly in inner lamina II neurons  of the dorsal horn; there is reduced neuropathic  and inflammatory  pain but preserved acute nocicep- tive pain in mice lacking PKCγ (Malmberg et al. 1997b). PKCγ expression is further  induced in the spinal cord by inflammation  and nerve injury (Mar- tin et al. 1999). The ε-isoform of PKC, in contrast,  is expressed in primary sensory neurons  and plays a major role in peripheral  sensitization  of noci- ceptor terminals  in inflammatory  and neuropathic  pain conditions  (Khasar et al. 1999).

Calcium/Calmodulin-Dependent Kinase This kinase (CaMK-II) has been inten- sively studied in hippocampal neurons and plays an essential role in synaptic plasticity and learning and memory. The active form of αCaMK-II autophos- phorylated  at threonine  286, a critical site for CaMK-II activation, has been

shown to enhance excitatory synaptic transmission  in dorsal horn  neurons

(Kolaj et al. 1994). The superficial  dorsal  horn  is densely stained  with an

anti-αCaMK-II antibody  (Fang et al. 2002; Zeitz et al. 2004). Recent stud- ies show that CaMK-II is required  for central sensitization  and neuropathic pain sensitization (Fang et al. 2002; Garry et al. 2003). Disruption of CaMK- II’s docking to the NMDA receptor  may be important  for the activation  of this receptor  and the subsequent  sensitization  of pain behavior after nerve injury  (Garry et al. 2003). However, in mice with a point  mutation  in the

αCaMK-II gene at threonine  286, inflammatory  pain and neuropathic  pain remain  unchanged  (Zeitz et al. 2004). The role of another  isoform, CaMK- IV, in pain  regulation  is unclear,  although  it is expressed  in 30% of DRG neurons and implicated in the activation of cAMP-response element binding

protein  (CREB), an important transcription factor for many neuronal  genes

(Ji et al. 1996).

Protein Kinase G (PKG)  Ca2+ influx through  the NMDA receptor activates the nitric  oxide/cGMP/PKG pathway. Neuronal  nitric  oxide synthase  (NOS) is Ca2+/calmodulin-dependent. Nitric oxide (NO) serves as a diffusible and retro- grade messenger. The major target of NO in the CNS appears is a soluble guany-

lyl cyclase (sGC) leading to the production of cyclic guanosine monophosphate (cGMP) and subsequent activation of PKG (Meller and Gebhart 1993). Nerve injury upregulates  NOS in DRG neurons  (Zhang et al. 1993). PKG appears to play a role in peripheral  and  central  sensitization  (Meller and  Gebhart

1993; Sluka and Willis 1997; Aley et al. 1998). PKG-I is expressed in the spinal cord, and mice lacking PKG-I show reduced inflammatory  hyperalgesia with preservation  of acute thermal nociception  (Tegeder et al. 2004a). In Aplysia sensory neurons, PKG-I couples to the ERK (extracellular signal-regulated ki- nase) pathway and contributes to axotomy-induced long-term hyperexcitabil- ity (Sung et al. 2004).

Other Kinases  The transcription factor nuclear factor NF-κB plays an important role in inflammatory responses by inducing the transcription of genes encod- ing many inflammatory  mediators. NF-κB is normally retained in cytoplasm by IκB inhibitor proteins. The phosphorylation of IκB by its kinase, IKK, results in IκB degradation.  IκB degradation  enables nuclear translocation  of NF-κB for gene transcription. Specific inhibition of IKK is shown to reduce both in- flammatory and neuropathic  pain (Tegeder et al. 2004b). Rho kinase (ROCK) is regarded  as a promising  drug target for neurological disorders  (Mueller et al. 2005). ROCK inhibitors were shown to suppress inflammatory and neu-

ropathic pain (Inoue et al. 2004; Tatsumi et al. 2005). Casein kinase 2 (CK2) is a widely expressed protein kinase and involved in central sensitization and inflammatory pain (Li et al. 2005). Although cyclin-dependent kinase 5 (Cdk5) is typically involved in cell division, recent evidence also suggests a role of this kinase in regulating neural plasticity in the brain. Intrathecal administra- tion of roscovitine, a Cdk5 inhibitor, attenuates formalin-induced  nociceptive response in rats (Wang et al. 2005).

Finally, it is worth  discussing phosphatidylinositol 3-kinase (PI3K) and the PI3K pathway. Although PI3K is a lipid kinase that phosphorylates the D-3 position of phosphatidylinositol lipids to produce PI(3,4,5)P3, acting asa mem- brane-embedded second messenger (Toker and Cantley 1997), PI3K behaves like a protein kinase. Another reason to include PI3K is that the downstream protein  kinase  Akt (protein  kinase  B) is a serine/threonine kinase  and  is postulated  to mediate  most of PI3K’s effects. Activation of Akt is typically used to examine the activation of PI3K pathway (Zhuang et al. 2004). PI3K is a major pathway activated by growth factors; therefore, NGF can strongly activate the PI3K pathway in DRG neurons.  PI3K is also activated in DRG

neurons  by C fiber activator  capsaicin  due  to intracellular  Ca2+  increase. PI3K inhibitors  prevent  heat hyperalgesia by both NGF and capsaicin. The PI3K is especially important for the induction  of heat hyperalgesia (Zhuang

et al. 2004).

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