Role of ryanodine receptors in neuronal calcium signalling and growth control

<p>The versatility of Ca²⁺ as a messenger regulating a myriad of signalling events requires that the concentration of Ca²⁺ ions in the cytoplasm be highly regulated. Capacitative Ca²⁺ entry (CCE) or store-operated Ca²⁺ (SOC) entry, whereby the depletion of intracellular Ca²⁺ stores induces the influx of Ca²⁺ across the plasma membrane, plays a crucial role in Ca²⁺ signalling. Despite the recent advances in elucidating the entry pathway, its molecular identity, biophysical properties and store-depletion signal remains undefined. Thapsigargin (TG), a sarcoplasmic/endoplasmic reticulum Ca²⁺ A TPase pump (SERCA), inhibitor induces passive depletion of the internal Ca²⁺ stores and triggers CCE. The universality of this signal has been widely accepted and TG has proven to be a valuable tool in studying CCE. The neuronal cell line NG 115 -401 L lacks the TG activated Ca²⁺ influx pathway. Agonists of the ryanodine receptor (RyR); chlorom- cresol (CMC), polychlorinated biphenyl 95 (PCB), ryanodine, caffeine, and that of the inositol-1 ,4 ,5-trisphosphate receptor (IP₃R), bradykinin, effectively couple to the activation of Ca²⁺ influx in these cells. The Ca²⁺ influx signal due to these agonists can be inhibited by SOC blockers such as La³⁺, Zn²⁺, Ni²⁺ and SF&F 96365. Thapsigargin, CMC and PCB95 share the same Ca²⁺ releasable pools in the 401 L cells. Our data thus suggests that the channels present in the 401 L cells are likely to be receptor-activated channels rather than the store-depletion activated channels. Cell viability studies show that thapsigargin (25 nM) can decrease viability by 75% within 24 hrs and the RyR agonist caffeine decreased viability to <60% within 24hrs. CMC, PCB95 and ryanodine also were cytotoxic at higher doses. Nuclear fragmentation patterns and activation of caspase-3 in thapsigargin and caffeine-treated cells suggest the induction of apoptosis within 12 hrs of treatment. The treated cells were shown to generate nitric oxide, a potential apoptosis inducing agent.</p>

Name thesis:degree_name

Master of Science (M.S.)

Level thesis:degree_level

Thesis - Pacific Access Restricted

Discipline thesis:degree_discipline

Pharmaceutical and Chemical Sciences

Year dc:date.available

2002

Author dc:creator

• Bose, Diptiman Dipen

Contributors dc:contributor

• David Thomas

• Cellular signal transduction
• Neural transmission Regulation
• Cells Growth Regulation
• Ryanodine
• Calcium in the body
• Calcium Physiological effect
• Medicine and Health Sciences
• Pharmacy and Pharmaceutical Sciences

Licence

• http://rightsstatements.org/vocab/InC/1.0/

Repository record dc:identifier

https://scholarlycommons.pacific.edu/uop_etds/566

OAI identifier oai:identifier

oai:scholarlycommons.pacific.edu:uop_etds-1565