Neurokinin A (NKA), formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflammatory and pain responses.
Introduction Neurokinin A (formerly known as substance K) is a member of the tachykinin family of neuropeptide neurotransmitters. Tachykinins are important contributors to nociceptive processing, satiety, and smooth muscle contraction. Tachykinins are known to be highly excitatory neurotransmitters in major central neural systems. Neurokinin A is ubiquitous in both the central and peripheral mammalian nervous systems, and seems to be involved in reactions to pain and the inflammatory responses. It is produced from the same preprotachykinin A gene as the neuropeptide substance P. Both substance P and neurokinin A are encoded by the same mRNA, which when alternatively spliced can be translated into either compound. It has various roles in the body of humans and other animals, specifically stimulation of extravascular smooth muscle, vasodilation, hypertensive action, immune system activation, and pain management. The deduced amino acid sequence of neurokinin A is as follows:
His Lys Thr Asp Ser Phe Val Gly Leu Met (HKTDSFVGLM) with amidation at the C-terminus.
Mechanism of action
Modified from: Sun J, Ramnath RD, Tamizhselvi R, Bhatia M."Neurokinin A engages neurokinin-1 receptor to induce NF-kappaB-dependent gene expression in murine macrophages: implications of ERK1/2 and PI 3-kinase/Akt pathways." Am J Physiol Cell Physiol. 2008 Sep;295(3):C679-91 Like Substance P [SP], Neurokinin A is present in excitatory neurons and secretory cells of the hypothalamic–pituitary–adrenal axis. Additionally both SP neurokinin A is found in the neurosensory system and modulates a wide range of inflammatory and tissue repairing processes [1]. In various tissues, such as the skin, the release of bioactive tachykinins by sensory nerve fibers C, that extend from the dorsal root ganglia into the epidermis, directly influence the activity of keratinocytes. Inflammation, tissue healing and cell proliferation have been linked to both SP and neurokinin A release into surrounding tissues.
Nervous system The overstimulation of the hypothalamic–pituitary–adrenal axis system and elevated secretion of corticotropin-releasing hormone from the hypothalamus, have been studied in many clinical manifestations of pathological depression. Studies have shown that stress-induced activation of the noradrenergic prefrontal lobe system may be under the control of both endogenously released corticotropin-releasing hormone and SP and neurokinin A. This study directly links the secretion of neurokinin A and SP to certain forms of depression characterized by the corticoid receptor hypothesis of depression. Inflammatory responses within the central nervous system (CNS) are often the result of traumatic injury or exposure to infectious agents. Inflammation provides a protective immune response to such stresses may also result in progressive damage to the CNS. There is significant evidence to indicate that tachykinins are a major component of the neural inflammatory response at peripheral tissues as well as the CNS. The ability to regulate tachykinin secretion represents an important mechanism for designing potentially useful drugs to treat inflammation. Neurokinin A has been associated with the chemokines interleukin-1 and interleukin-6, both of which are heavily involved in the inflammatory process during infections. Neuronal tissue can be severely damaged either through physical trauma or intracellular stresses, either chronic or acute. Either of these scenarios can result in calcium overload, protein degradation, the unfolded protein response or an accumulation of DNA damage. Endogenous cellular responses are activated within nerve tissue in response to damage in order to protect cellular, protein, and nucleic acid integrity. A large variety of neuroprotective signaling mechanisms exist, which can be manipulated by drugs to reduce damage from cellular damage in neurons. Tachykinins thus have a number of neuroprotective physiological roles in medical conditions
Immune system The immune system is a highly integrated system which receives input from many sources, such as sites of injury, nociceptors and white blood cells. Chemical signals therefore are an important component of paracrine, autocrine and endocrine signaling. Neurokinin A was shown to be a potent chemo attractor for T-cells increasing the migration into infected tissues. This migration is necessary for the pathogen seeking activity of T-cells. Some chemokines trigger the intravascular adhesion of T-cells whereas others direct the migration of leukocytes into and within the extravascular space. Since lymphocytes must be positioned correctly to interact with other cells, the pattern of chemokine receptors and the type and distribution of chemokines in tissues critically influence immune responses. The molecular mechanism behind neurokinin's role as a chemoattractor is currently unclear. Neurokinin A has an inhibitory effect on the formation of myeloid cells, and appear to be involved in one specific receptor since the effect can be completely abolished by a NK-2 receptor-selective antagonist. The inhibitory effect of neuronkinin A is countered by the excitatory effect of a structurally similar compound: substance P. The opposite effects on myelogenesis by substance P and neurokinin A may represent an important feedback mechanism for maintenance of homeostasis.
Respiratory system The binding of neurokinin A to the NKR-2 results in bronchoconstriction, mucus production in the lungs and process neurogenic inflammation. This release is propagated through the stimulation of e-NANC nerves in the bronchial epithelium via an axon-reflex mechanism.
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