NK1R-mediated Non-Apoptotic PCD
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NK1R-mediated Non-Apoptotic PCD

Cell death has been divided into two main types: PCD (Programmed Cell Death), in which the cell plays an active role, and Necrotic (passive) cell death. PCD is a form of cell death in which the cell plays an active role in its own demise. In contrast, Necrosis is characterized by swelling of the cell and its organelles; that results in disruption of the cell membrane and cell lysis. The PCD observed during development and tissue homeostasis has been classified morphologically into three main types: type 1, also known as nuclear or apoptotic; type 2 or Autophagic; and type 3, also referred to as Cytoplasmic. Apoptosis is the best characterized type of PCD, in which the cells display membrane blebbing, flipping of Phosphatidylserine in the plasma membrane, nuclear fragmentation, and activation of a family of cell suicide cysteine proteases, referred to as Caspases (Ref.1). Although PCD has often been equated with Apoptosis, it has now become clear that nonapoptotic forms of PCD (Autophagic and Cytoplasmic cell death) are equally important. Neurodegenerative diseases such as Huntingtons disease and Amyotrophic Lateral Sclerosis demonstrate neuronal cell death that does not fulfill the criteria for Apoptosis but instead resembles a recently described form of PCD, dubbed, Paraptosis. Ischemia-induced cell death may also display a nonapoptotic morphology, referred to as "oncosis". The biochemical basis for these alternative morphological forms of cell death remains largely unknown. Understanding the mechanisms for these forms would have potentially important implications for the understanding of evolutionary aspects of cell death programs, developmental cell death, neurodegeneration, and cancer therapeutics and for the design of novel therapeutic agents for diseases featuring these alternative forms of cell death (Ref.1&2).

Much less is known about the biochemical mediators of type 2 and type 3 PCD, i.e., nonapoptotic PCD. Type 2 cell death can be activated in some cases by Ras, whereas the molecular activation of type 3 cell death is unknown. Recently, it was noted that the binding of the undecapeptide neurotransmitter Tac1 (Tachykinin-1)/Substance-P to its receptor, NK1R (Neurokinin-1 Receptor)/ TacR1 (Tachykinin Receptor-1), induces a nonapoptotic form of PCD resembling type 2 or 3 morphologically and characterized by cytoplasmic vacuolation, lack of Caspase activation, lack of nuclear fragmentation or membrane blebbing, and a requirement for new gene transcription and translation (Ref.1). This ligand-receptor pair is widely distributed in the central and peripheral nervous systems, and has been implicated in pain mediation and depression, among other effects. NK1R is a GPCR (G-Protein Coupled Receptor) that is connected by various second messengers to a wide variety of effector mechanisms to modulate cellular function. Tac1 is an undecapeptide that is produced by the post-translational modification of preprotachykinin-A in sensory nerves. Upon its release, Tac1 preferentially acts on the NK1R to produce nonapoptotic cell death, and its other proinflammatory effects. For example, Tac1 is a potent mediator of increased microvascular permeability, leading to inflammatory swelling, through its action on NK1R on post-capillary endothelial cells. Furthermore, Tac1 has a potent effect on inflammatory cell accumulation and causes vasodilation in larger blood vessels (Ref.3).

This form of nonapoptotic PCD through the Tac1-NK1R ligand-receptor complex is mediated by a MAPK phosphorylation cascade recruited by the scaffold protein Arr2 (Arrestin-2). The activation of the protein kinases Raf1, MEK2 (MAPK/ERK Kinase-2), and ERK2 (Extracellular Signal-Regulated Kinase-2) is essential for this pathway, leading to the phosphorylation of the orphan nuclear receptor Nur77 (Ref.4). Upon Tac1 binding to NK1R, Arr2 interacts with the carboxyl-terminal region of NK1R and recruits a MAPK complex that triggers the phosphorylation cascade of Raf1, MEK2, and ERK2, which targets Nur77 in both neuronal and nonneuronal cells. Nur77 phosphorylation by ERK2 may take place directly or indirectly, and is essential for the progression to cell death, referred to as nonapoptotic PCD. Nur77, as a downstream effector of ERK2 activation (be it direct or indirect) is of potential interest, since its induction has been reported in situations in which neuronal death occurs, such as Kainic acid-induced seizures and ischemic brain injury. It is a pivotal modulator of cell fate (Ref.1). Thus, NK1R plays a pivotal role in the nonapoptotic PCD of both neuronal and nonneuronal cells, through the phosphorylation of Nur77. It plays an important role in pathological states in which neural cell death occurs, such as status epilepticus and ischemia. The development of specific agonists and antagonists for NK1R has supported a role for NK1R in numerous biological processes, such as the transmission of pain in the spinal cord. In the central nervous system, it also regulates cardiovascular and respiratory function and is involved in activating the emetic reflex. NK1R also regulates several behavioral responses and has recently been implicated in depression and schizophrenia. It appears to be involved in a wide variety of functions due to its ability to modulate the release of other neurotransmitters, such as excitatory amino acids (Ref.2&4).