The ERK 1 and 2 pathway in the nervous system: from basic aspects to possible clinical applications in pain and visceral dysfunction

Abstract

The extracellular signal-regulated kinases 1 and 2 (ERK) cascade, member of the mitogen-activated protein kinases superfamily of signalling pathways, is one of the best characterized pathways as many protein interactions and phosphorylation events have been systematically studied. Traditionally, ERK are associated with the regulation of proliferation and differentiation as well as survival of various cell types. Their activity is controlled by phosphorylation on specific aminoacidic residues, which is induced by a variety of external cues, including growth-promoting factors.In the nervous system, ERK phosphorylation is induced by binding of neurotrophins to their specific tyrosine kinase receptors or by neuronal activity leading to glutamate release and binding to its ionotropic and metabotropic receptors. Some studies have provided evidence of its importance in neuroplastic events. In particular, ERK phosphorylation in the spinal cord was shown to be nociceptive-specific and its upregulation, occurring in cases of chronic inflammatory and neuropathic pain, seems to be of the utmost importance to behavioural changes observed in those conditions. In fact, experiments using specific inhibitors of ERK phosphorylation have proved that ERK directly contributes to allodynia and hyperalgesia caused by spinal cord injury or chronic pain. Additionally, spinal ERK phosphorylation regulates the micturition reflex in experimental models of bladder inflammation and chronic spinal cord transection.In this review we will address the main findings that suggest that ERK might be a future therapeutic target to treat pain and other complications arising from chronic pain or neuronal injury.

Keywords: ERK; ERK inhibition; MAPK; pain.; somatic pain; visceral pain; visceral reflex activity.

Fig. (1)

The MAPK family with its classical cascades, the ERK 1 and 2,p38 and JNK. (A) The MAPK family of signalling pathways is characterized by a central motif of three kinases, which activate each other in a sequential order by phosphorylation of specific residues. Classically, 3 distinct pathways are included in the MAPK family (the ERK 1 and 2, p38 and JNK),the activation of which leads to different cellular outcomes. (B) The activation of the ERK pathway depends on a variety of membrane bound receptors,including growth factor receptors, G protein coupled receptors (GPCRs), the estrogen receptor and ionic channels. In some cases, binding of certain cytokines to their specific receptor may also lead to the activation of this pathway. Once active (that is, phosphorylated) ERK can target a variety of nuclear and cytoplasmic elements.

Fig. (2)

PhosphoERK immunoreactive neurons in sections from the L6 dorsal root ganglion (A) and spinal cord (B). Animals were submitted to acute noxious bladder distension. ERK activation occurred mostly in smallto medium diameter neurons (A, arrows), most likely nociceptive neurons.In the spinal cord (B), immunoreactive neurons were located bilaterally in the superficial laminae of the cord, in the dorsal commissure and in the intermediolateral grey matter, areas known to receive bladder sensory input (Cruz et al., unpublished observations).

Fig. (3)

Mechanisms of ERK activation in the spinal cord. Upon noxious peripheral stimulation, glutamate and BDNF are released onto the spinal cord. Upon binding to their respective receptors, activation of the pathway occurs in the cytoplasm of spinal neurons. Once activated, ERK can modulate the activity of membrane receptors by phosphorylating specific subunits. Activated ERK can also translocate to the nucleus and induce gene transcription by phosphorylation of transcription factors. The importance of substance P is still in debate.

Fig. (4)

Preventing ERK activation with PD98059. The most commonly used approach to avert ERK phosphorylation consists in blocking the interaction between phosphorylated MEK and inactive ERK. Several inhibitors have been developed to accomplish this task, the most frequently used of which is PD98059. This inhibitor is a non-competitive cyclic molecule with an amino moiety.

Fig. (5)

Reduction of allodynia in animals with chronic joint inflammation following administration of ERK inhibitor. In (A), U0126 (another ERK inhibitor) was delivered an intra-articular injection. As a consequence, the angle of knee movement, which was less than 70% of control, was improved with the administration of 1 and 10µg of intra-articular inhibitor. Adapted from [95]. In (B), ankle-bend scores for saline- and intrathecal injected PD98059 in monoarthritic (MA) rats at different time points. The anklebend test for MA rats was performed immediately before the intrathecal injection (time 0) of either saline (control; black circles) or 1 µg (grey squares) and 2 µg (white triangles) of PD98059 in MA rats with 4 and 14 days of evolution, respectively. The high struggle scores induced by ankle bending observed in control MA animals was increased thought-out the all experimental period. On the contrary, ankle-bend scores for the PD98059 injected groups were significantly decreased. Adapted from [27]. CD Cruz,Pain (2005) 116:411-419. Used with permission. D Seino, Pain (2006)123:193-203. Used with permission.

Fig. (6)

Effect of intrathecal administration of PD98059 on bladder reflex activity in animals with intact and chronically transected spinal cord. In animals with intact cords, PD98059 had no effect in bladder contractions,despite the amount of inhibitor injected. In animals that underwent chronic spinal cord transection at high thoracic levels, bladder reflex activity is clearly altered. These animals display high frequency of bladder contractions with strong micturition pressures. PD98059 visibly reduced both the frequency and amplitude of bladder contractions (Cruz et al., unpublished results).