Calcium is a crucial intracellular messenger controlling a plethora of important intracellular events. Elevated [Ca2+]i levels regulate numerous processes due to the versatility of the Ca2+ signaling in terms of speed, amplitude and spatia-temporal patterning. Depletion of intracellular calcium stores functions as a primary trigger for a message that is translated to the plasma membrane, resulting in the slow activation of plasma membrane Ca2+ influx channels, which allow entry of external calcium. Since these channels depend upon the state of filling of the intracellular Ca2+stores, these influx channels are called store-operated channels (SOCs). It is unclear how empty intracellular stores signal activation of plasma membrane capacitative calcium entry (CCE). In order to bridge the gaps in our understanding of calcium's role in T cell regulation, this project was designed to look at the effects of various pharmacological regulators of T cell calcium stores. At the start, the effort was directed at the regulation of the microsomal calcium A TPases, considering these are perhaps the most essential mediators of intracellular calcium storage. Thapsigargin (TG) and cyclopiazonic acid (CPA) were shown to be the most potent inhibitors of the Ca2+ -ATPase, also a new Ca2+ regulator aaptamine was shown to exert more modest inhibition of the Ca2+ pump. We also characterized a novel compound, gingerol, findings its actions are to stimulate Ca2+ pumps. Cell growth assays revealed an important role for ryanodine receptors (RyRs) in regulating T cell growth. RyR activators CMC and PCB95 dramatically altered T cell growth patterns leading to significantly reduced cell viability. In contrast RyR antagonist dantrolene appeared to induce growth arrest in that cell proliferation was curtailed, yet cells remained viable.
Cell viability studies revealed that the Ca2+ pump regulators TG and aaptamine were also observed to reduce cell growth rates, presumably as a result of their ability to deplete Ca2+ stores (100 nM TG was able to decrease cell viability by 90% within 24 hrs of exposure). PCB95 was able to decrease cell viability by 50% within 24 of hrs exposure and CMC decreased cell viability by 75% within 24 hrs and further over a 48 hr period. 2-APB and aaptamine were cytotoxic at higher doses. The inositol 1 ,4,5 -trisphosphate receptor (IP3R) pathway was also found to be critically linked to T cell growth control. We observed that the IP3R modulator, 2- aminoethoxydiphenyl borate (2-APB) induced antigen-like Ca2+ spike that correlates with suppression of T cell growth rates.
In this study we have identified two novel T cell Ca2+ store regulators, aaptamine and gingerol. We also find that Ca2+ stores are indeed sensitively linked to T cell growth regulation. Depletion of Ca2+ stores with SERCA inhibitors as well as both RyR and IP3R activators profoundly suppress T cell proliferation most likely via activation of apoptosis.
","abstract_html":"<p>Calcium is a crucial intracellular messenger controlling a plethora of important intracellular events. Elevated [Ca<sup>2+</sup>]i levels regulate numerous processes due to the versatility of the Ca<sup>2+</sup> signaling in terms of speed, amplitude and spatia-temporal patterning. Depletion of intracellular calcium stores functions as a primary trigger for a message that is translated to the plasma membrane, resulting in the slow activation of plasma membrane Ca<sup>2+</sup> influx channels, which allow entry of external calcium. Since these channels depend upon the state of filling of the intracellular Ca<sup>2+</sup>stores, these influx channels are called store-operated channels (SOCs). It is unclear how empty intracellular stores signal activation of plasma membrane capacitative calcium entry (CCE). In order to bridge the gaps in our understanding of calcium's role in T cell regulation, this project was designed to look at the effects of various pharmacological regulators of T cell calcium stores. At the start, the effort was directed at the regulation of the microsomal calcium A TPases, considering these are perhaps the most essential mediators of intracellular calcium storage. Thapsigargin (TG) and cyclopiazonic acid (CPA) were shown to be the most potent inhibitors of the Ca<sup>2+</sup> -ATPase, also a new Ca<sup>2+</sup> regulator aaptamine was shown to exert more modest inhibition of the Ca<sup>2+</sup> pump. We also characterized a novel compound, gingerol, findings its actions are to stimulate Ca<sup>2+</sup> pumps. Cell growth assays revealed an important role for ryanodine receptors (RyRs) in regulating T cell growth. RyR activators CMC and PCB95 dramatically altered T cell growth patterns leading to significantly reduced cell viability. In contrast RyR antagonist dantrolene appeared to induce growth arrest in that cell proliferation was curtailed, yet cells remained viable.</p> <p>Cell viability studies revealed that the Ca<sup>2+</sup> pump regulators TG and aaptamine were also observed to reduce cell growth rates, presumably as a result of their ability to deplete Ca<sup>2+</sup> stores (100 nM TG was able to decrease cell viability by 90% within 24 hrs of exposure). PCB95 was able to decrease cell viability by 50% within 24 of hrs exposure and CMC decreased cell viability by 75% within 24 hrs and further over a 48 hr period. 2-APB and aaptamine were cytotoxic at higher doses. The inositol 1 ,4,5 -trisphosphate receptor (IP<sub>3</sub>R) pathway was also found to be critically linked to T cell growth control. We observed that the IP3R modulator, 2- aminoethoxydiphenyl borate (2-APB) induced antigen-like Ca<sup>2+</sup> spike that correlates with suppression of T cell growth rates.</p> <p>In this study we have identified two novel T cell Ca<sup>2+</sup> store regulators, aaptamine and gingerol. We also find that Ca<sup>2+</sup> stores are indeed sensitively linked to T cell growth regulation. Depletion of Ca<sup>2+</sup> stores with SERCA inhibitors as well as both RyR and IP<sub>3</sub>R activators profoundly suppress T cell proliferation most likely via activation of apoptosis.</p>","abstract_has_math":false,"creators":["Peters, Alister Michael"],"institution":null,"degree_name":"Master of Science (M.S.)","degree_level":"Thesis - Pacific Access Restricted","degree_discipline":"Pharmaceutical and Chemical Sciences","degree_department":null,"school":null,"contributors":["David Thomas"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2004,"date_issued":"2004-01-01T08:00:00Z","date_published":"2004-01-01T08:00:00Z","updated_at":"2026-07-24T05:36:35Z","subjects":["T cells Growth Regulations","Cellular control mechanisms","Calcium in the body","Growth regulators","Medicinal and Pharmaceutical Chemistry","Medicine and Health Sciences","Pharmacy and Pharmaceutical Sciences"],"languages":[],"rights":[],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[]},"links":{"outbound_url":"https://scholarlycommons.pacific.edu/uop_etds/596","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["David Thomas"]},{"key":"dc:creator","label":"Author","values":["Peters, Alister Michael"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2018-06-29T08:50:30Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmaceutical and Chemical Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Thesis - Pacific Access Restricted"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Master of Science (M.S.)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["T cells Growth Regulations","Cellular control mechanisms","Calcium in the body","Growth regulators","Medicinal and Pharmaceutical Chemistry","Medicine and Health Sciences","Pharmacy and Pharmaceutical Sciences"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["http://rightsstatements.org/vocab/InC/1.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://scholarlycommons.pacific.edu/uop_etds/596"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Calcium is a crucial intracellular messenger controlling a plethora of important intracellular events. Elevated [Ca2+]i levels regulate numerous processes due to the versatility of the Ca2+ signaling in terms of speed, amplitude and spatia-temporal patterning. Depletion of intracellular calcium stores functions as a primary trigger for a message that is translated to the plasma membrane, resulting in the slow activation of plasma membrane Ca2+ influx channels, which allow entry of external calcium. Since these channels depend upon the state of filling of the intracellular Ca2+stores, these influx channels are called store-operated channels (SOCs). It is unclear how empty intracellular stores signal activation of plasma membrane capacitative calcium entry (CCE). In order to bridge the gaps in our understanding of calcium's role in T cell regulation, this project was designed to look at the effects of various pharmacological regulators of T cell calcium stores. At the start, the effort was directed at the regulation of the microsomal calcium A TPases, considering these are perhaps the most essential mediators of intracellular calcium storage. Thapsigargin (TG) and cyclopiazonic acid (CPA) were shown to be the most potent inhibitors of the Ca2+ -ATPase, also a new Ca2+ regulator aaptamine was shown to exert more modest inhibition of the Ca2+ pump. We also characterized a novel compound, gingerol, findings its actions are to stimulate Ca2+ pumps. Cell growth assays revealed an important role for ryanodine receptors (RyRs) in regulating T cell growth. RyR activators CMC and PCB95 dramatically altered T cell growth patterns leading to significantly reduced cell viability. In contrast RyR antagonist dantrolene appeared to induce growth arrest in that cell proliferation was curtailed, yet cells remained viable.
Cell viability studies revealed that the Ca2+ pump regulators TG and aaptamine were also observed to reduce cell growth rates, presumably as a result of their ability to deplete Ca2+ stores (100 nM TG was able to decrease cell viability by 90% within 24 hrs of exposure). PCB95 was able to decrease cell viability by 50% within 24 of hrs exposure and CMC decreased cell viability by 75% within 24 hrs and further over a 48 hr period. 2-APB and aaptamine were cytotoxic at higher doses. The inositol 1 ,4,5 -trisphosphate receptor (IP3R) pathway was also found to be critically linked to T cell growth control. We observed that the IP3R modulator, 2- aminoethoxydiphenyl borate (2-APB) induced antigen-like Ca2+ spike that correlates with suppression of T cell growth rates.
In this study we have identified two novel T cell Ca2+ store regulators, aaptamine and gingerol. We also find that Ca2+ stores are indeed sensitively linked to T cell growth regulation. Depletion of Ca2+ stores with SERCA inhibitors as well as both RyR and IP3R activators profoundly suppress T cell proliferation most likely via activation of apoptosis.
"]},{"key":"dc:source","label":"Dc Source","values":["98"]},{"key":"dc:title","label":"Title","values":["Pharmacological regulators of T cell calcium stores"]}]}],"canonical_facts":{"dc:contributor":["David Thomas"],"dc:creator":["Peters, Alister Michael"],"dc:date.available":["2018-06-29T08:50:30Z"],"dc:description.abstract":["Calcium is a crucial intracellular messenger controlling a plethora of important intracellular events. Elevated [Ca2+]i levels regulate numerous processes due to the versatility of the Ca2+ signaling in terms of speed, amplitude and spatia-temporal patterning. Depletion of intracellular calcium stores functions as a primary trigger for a message that is translated to the plasma membrane, resulting in the slow activation of plasma membrane Ca2+ influx channels, which allow entry of external calcium. Since these channels depend upon the state of filling of the intracellular Ca2+stores, these influx channels are called store-operated channels (SOCs). It is unclear how empty intracellular stores signal activation of plasma membrane capacitative calcium entry (CCE). In order to bridge the gaps in our understanding of calcium's role in T cell regulation, this project was designed to look at the effects of various pharmacological regulators of T cell calcium stores. At the start, the effort was directed at the regulation of the microsomal calcium A TPases, considering these are perhaps the most essential mediators of intracellular calcium storage. Thapsigargin (TG) and cyclopiazonic acid (CPA) were shown to be the most potent inhibitors of the Ca2+ -ATPase, also a new Ca2+ regulator aaptamine was shown to exert more modest inhibition of the Ca2+ pump. We also characterized a novel compound, gingerol, findings its actions are to stimulate Ca2+ pumps. Cell growth assays revealed an important role for ryanodine receptors (RyRs) in regulating T cell growth. RyR activators CMC and PCB95 dramatically altered T cell growth patterns leading to significantly reduced cell viability. In contrast RyR antagonist dantrolene appeared to induce growth arrest in that cell proliferation was curtailed, yet cells remained viable.
Cell viability studies revealed that the Ca2+ pump regulators TG and aaptamine were also observed to reduce cell growth rates, presumably as a result of their ability to deplete Ca2+ stores (100 nM TG was able to decrease cell viability by 90% within 24 hrs of exposure). PCB95 was able to decrease cell viability by 50% within 24 of hrs exposure and CMC decreased cell viability by 75% within 24 hrs and further over a 48 hr period. 2-APB and aaptamine were cytotoxic at higher doses. The inositol 1 ,4,5 -trisphosphate receptor (IP3R) pathway was also found to be critically linked to T cell growth control. We observed that the IP3R modulator, 2- aminoethoxydiphenyl borate (2-APB) induced antigen-like Ca2+ spike that correlates with suppression of T cell growth rates.
In this study we have identified two novel T cell Ca2+ store regulators, aaptamine and gingerol. We also find that Ca2+ stores are indeed sensitively linked to T cell growth regulation. Depletion of Ca2+ stores with SERCA inhibitors as well as both RyR and IP3R activators profoundly suppress T cell proliferation most likely via activation of apoptosis.
"],"dc:identifier":["https://scholarlycommons.pacific.edu/uop_etds/596"],"dc:rights":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:source":["98"],"dc:subject":["T cells Growth Regulations","Cellular control mechanisms","Calcium in the body","Growth regulators","Medicinal and Pharmaceutical Chemistry","Medicine and Health Sciences","Pharmacy and Pharmaceutical Sciences"],"dc:title":["Pharmacological regulators of T cell calcium stores"],"thesis:degree_discipline":["Pharmaceutical and Chemical Sciences"],"thesis:degree_level":["Thesis - Pacific Access Restricted"],"thesis:degree_name":["Master of Science (M.S.)"]},"updated_at":"2026-07-24T05:36:35Z"}