Neurobiology of substance P and the NK1 receptor.
Substance P belongs to a group of neurokinins (NKs), small peptides that are broadly distributed in the central nervous system (CNS) and peripheral nervous system (PNS). The biological effects of substance P in the CNS, namely regulation of affective behavior and emesis in the brain and nociception in the spinal cord, are mediated by its binding to the NK1 receptor. The substance P-NK1 (SP-NK1) receptor system is the most extensively studied NK pathway, and in contrast to receptors for other neurotransmitters, such as glutamate, which have high expression throughout the CNS, only a minority of neurons (5% to 7%) in certain CNS areas express the NK1 receptor. The NK1 receptor is distributed in the plasma membrane of cell bodies and dendrites of unstimulated neurons, but upon substance P binding, the NK1 receptor undergoes rapid internalization, followed by rapid recycling to the plasma membrane. Release of substance P is induced by stressful stimuli, and the magnitude of its release is proportional to the intensity and frequency of stimulation. More potent and more frequent stimuli allow diffusion of substance P farther from the site of release, allowing activation of an approximately 3- to 5-times greater number of NK1 receptor-expressing neurons. Recent studies employing pharmacologic or genetic inactivation of NK1 receptors demonstrate the important role of the SP-NK1 receptor system in the regulation of affective behavior and suggest that inhibition of this pathway may be a useful approach to treatment of depression and associated anxiety.
Mantyh
Patrick W
PW
Department of Preventive Sciences, Psychiatry, and Neuroscience, University of Minnesota, Minneapolis, USA. manty001@umn.edu
D000339:Affect / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001008:Anxiety Disorders / Q000188:drug therapy / Q000503:physiopathology; D001921:Brain / Q000166:cytology / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003866:Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D051379:Mice; D023421:Models, Animal; D051381:Rats; D011971:Receptors, Immunologic / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives / Q000187:drug effects / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*
D000928:Antidepressive Agents; D000922:Immunotoxins; D011971:Receptors, Immunologic; D018040:Receptors, Neurokinin-1; D054789:Ribosome Inactivating Proteins, Type 1; C468274:substance P-saporin; D013373:Substance P; D000076985:Saporins