Structural, Functional and Molecular Aspects of the Type 1 Sigma Receptor

Hdl Handle:
http://hdl.handle.net/10675.2/575221
Title:
Structural, Functional and Molecular Aspects of the Type 1 Sigma Receptor
Authors:
Seth, Pankaj
Abstract:
The most important results o f the studies described here include the following: i) the sigma receptor expressed in the central nervous system is identical at the molecular level with the sigma receptor expressed in peripheral tissues, ii) the cloned receptor represents the type 1 subtype based on its pharmacological characteristics, iii) the mouse gene coding for sigma receptor is — 7kb long and its structural organzation is similar to that of the human gene, iv) progesterone is an andogenous ligand for the cloned sigma receptor and the Kd for the interaction with this steroid hormone is -9 0 nM, v) several neurosteroids also interact with the receptor, but with comparitively lower affinities, and vi) essential anionic aminoacids are present in the ligand-binding site o f the receptor as evidenced from chemical modification and site-directed mutagenesis. Sigma receptors are receiving increased attention due to their involvement in a wide variety of functions associated with the endocrine, immune and central nervous system. These receptors interact with various antipsychotic drugs such as haloperidol and rimcazole. Sigma receptor has been linked to the pathogenesis o f psychiatric disorder (Itzahak and stein 1990). The human gene coding for the cloned type 1 sigma receptor is located on chromosome 9pl3, a region closely linked to the psychiatric disorder schizophrenia (Nanko et al., 1993). Even though the current literature points to (Rao, 1997), it is interesting to note that aberations in dopaminergic pathways are most likely involved in the pathogenesis o f schizophrenia. The findings that progesterone may be the endogenous ligand for the sigma receptor are o f significance to physiological conditions associated with elevated levels of progesterone. The Kd for interaction of this steroid hormone with sigma receptor is ~ 90 nM where as physiological concentrations o f the hormone are in range o f 30-40 nM under most circumstances. Under these conditions there may not be sufficient levels of progesterone to stimulate significant signalling via sigma receptor by progesterone. But, during pregnancy, the plasma levels o f progesterone rise to as high as 500 nM in women (Johansson, 1969). There is also significant cyclic fluctuations in progesterone levels in the circulation during menstrual cycle. This would mean that the biological effects of progesterone that are mediated by the interaction o f this steroid with type 1 sigma receptor may vary in magnitude in women under different physiological conditions, determined by the levels of progesterone. Progesterone has been shown to be active in anti-inflammatory tests and has been suggested to be Nature’s immunosuppressant that is responsible for the maternal tolerance of the placenta allograft during pregnancy (Siiteri, 1977). A direct comparison between the relative affinities o f various steroids for type 1 sigma receptor and the relative potencies of these steroids in anti-inflammatory test has suggested that the immunomodulatory effects of progesterone are likely to be produced through the sigma receptor (Su et al., 1988, Siiteri, 1977). These observations are especially relevant to pregnancy when the circulating levels of progesterone are high enough to saturate the type 1 sigma receptor in immune cells and cause immune suppression. This effect may be maximal at the maternal-placental interface at which progesterone secreted by placental trophoblasts is likely to be present at high level. There is also increasing evidence that the placenta may be the direct target of cocaine action (Ganapathy and Leibach, 1994). Therefore the interaction o f progesterone with the type 1 sigma receptor expressed in placental syncytiotrophoblast m ay provide an insight into the cellular mechanisms involved in the deleterious influence o f cocaine on the mother and her fetus seen in mothers abusing cocaine during pregnancy. The type 1 sigma receptor is a relatively small protein consisting of 223 amino acids. The molecular mass o f the protein is ~ 25 kDa. It does have a transmembrane domain and thus is an integral membrane protein. But, its presence is not restricted to any specific membrane compartment in most cells. In the placenta, sigma ligand-binding sites are detectable in the plasma membrane as well as in crude membranes with no appreciable difference in specific activity. Interestingly, this receptor is highly conserved across different animal species. But, it has no homology to any other known mammalian protein. A yeast enzyme involved in synthesis of ergosterol, a C8-C7 isomerase, appears to be structurally related to the mammalian sigma receptor (Hanner et al., 1996). However, the cloned sigma receptor protein shows no activity for C8-C7 isomerase (Hanner et al., 1996). Nontheless, it is however intriguing that yeast C8-C7 isomerase, human C8-C7 isomerase, and mammalian sigma receptor possess the ability to bind several drugs with comparable affinity (Moebius et al., 1997). The elucidation of the structure and choromosomal localization of the human gene and the ongoing efforts in the direction of sigma receptor knock-out mouse model, along with the knowledge of various putative functions that are associated with sigma receptor would certainly provide more information regarding the significance o f this receptor in diverse cellular functions.
Affiliation:
Not Listed
Issue Date:
1999
URI:
http://hdl.handle.net/10675.2/575221
Additional Links:
http://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/304541329?accountid=12365
Type:
Dissertation
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorSeth, Pankajen
dc.date.accessioned2015-08-18T22:56:59Zen
dc.date.available2015-08-18T22:56:59Zen
dc.date.issued1999en
dc.identifier.urihttp://hdl.handle.net/10675.2/575221en
dc.description.abstractThe most important results o f the studies described here include the following: i) the sigma receptor expressed in the central nervous system is identical at the molecular level with the sigma receptor expressed in peripheral tissues, ii) the cloned receptor represents the type 1 subtype based on its pharmacological characteristics, iii) the mouse gene coding for sigma receptor is — 7kb long and its structural organzation is similar to that of the human gene, iv) progesterone is an andogenous ligand for the cloned sigma receptor and the Kd for the interaction with this steroid hormone is -9 0 nM, v) several neurosteroids also interact with the receptor, but with comparitively lower affinities, and vi) essential anionic aminoacids are present in the ligand-binding site o f the receptor as evidenced from chemical modification and site-directed mutagenesis. Sigma receptors are receiving increased attention due to their involvement in a wide variety of functions associated with the endocrine, immune and central nervous system. These receptors interact with various antipsychotic drugs such as haloperidol and rimcazole. Sigma receptor has been linked to the pathogenesis o f psychiatric disorder (Itzahak and stein 1990). The human gene coding for the cloned type 1 sigma receptor is located on chromosome 9pl3, a region closely linked to the psychiatric disorder schizophrenia (Nanko et al., 1993). Even though the current literature points to (Rao, 1997), it is interesting to note that aberations in dopaminergic pathways are most likely involved in the pathogenesis o f schizophrenia. The findings that progesterone may be the endogenous ligand for the sigma receptor are o f significance to physiological conditions associated with elevated levels of progesterone. The Kd for interaction of this steroid hormone with sigma receptor is ~ 90 nM where as physiological concentrations o f the hormone are in range o f 30-40 nM under most circumstances. Under these conditions there may not be sufficient levels of progesterone to stimulate significant signalling via sigma receptor by progesterone. But, during pregnancy, the plasma levels o f progesterone rise to as high as 500 nM in women (Johansson, 1969). There is also significant cyclic fluctuations in progesterone levels in the circulation during menstrual cycle. This would mean that the biological effects of progesterone that are mediated by the interaction o f this steroid with type 1 sigma receptor may vary in magnitude in women under different physiological conditions, determined by the levels of progesterone. Progesterone has been shown to be active in anti-inflammatory tests and has been suggested to be Nature’s immunosuppressant that is responsible for the maternal tolerance of the placenta allograft during pregnancy (Siiteri, 1977). A direct comparison between the relative affinities o f various steroids for type 1 sigma receptor and the relative potencies of these steroids in anti-inflammatory test has suggested that the immunomodulatory effects of progesterone are likely to be produced through the sigma receptor (Su et al., 1988, Siiteri, 1977). These observations are especially relevant to pregnancy when the circulating levels of progesterone are high enough to saturate the type 1 sigma receptor in immune cells and cause immune suppression. This effect may be maximal at the maternal-placental interface at which progesterone secreted by placental trophoblasts is likely to be present at high level. There is also increasing evidence that the placenta may be the direct target of cocaine action (Ganapathy and Leibach, 1994). Therefore the interaction o f progesterone with the type 1 sigma receptor expressed in placental syncytiotrophoblast m ay provide an insight into the cellular mechanisms involved in the deleterious influence o f cocaine on the mother and her fetus seen in mothers abusing cocaine during pregnancy. The type 1 sigma receptor is a relatively small protein consisting of 223 amino acids. The molecular mass o f the protein is ~ 25 kDa. It does have a transmembrane domain and thus is an integral membrane protein. But, its presence is not restricted to any specific membrane compartment in most cells. In the placenta, sigma ligand-binding sites are detectable in the plasma membrane as well as in crude membranes with no appreciable difference in specific activity. Interestingly, this receptor is highly conserved across different animal species. But, it has no homology to any other known mammalian protein. A yeast enzyme involved in synthesis of ergosterol, a C8-C7 isomerase, appears to be structurally related to the mammalian sigma receptor (Hanner et al., 1996). However, the cloned sigma receptor protein shows no activity for C8-C7 isomerase (Hanner et al., 1996). Nontheless, it is however intriguing that yeast C8-C7 isomerase, human C8-C7 isomerase, and mammalian sigma receptor possess the ability to bind several drugs with comparable affinity (Moebius et al., 1997). The elucidation of the structure and choromosomal localization of the human gene and the ongoing efforts in the direction of sigma receptor knock-out mouse model, along with the knowledge of various putative functions that are associated with sigma receptor would certainly provide more information regarding the significance o f this receptor in diverse cellular functions.en
dc.relation.urlhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/304541329?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjectSigma Receptoren
dc.subjectPsychotomimetic Effectsen
dc.titleStructural, Functional and Molecular Aspects of the Type 1 Sigma Receptoren
dc.typeDissertationen
dc.contributor.departmentNot Listeden
dc.description.advisorGanapathy, Vadivelen
dc.description.committeeLeibach, F. H.; Lanclos, K.; Lewis, D.; Prasad, P.D.en
dc.description.degreeDoctor of Philosophy (Ph.D.)en
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