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Title: Regulation of inositol triphosphate receptors by calmodulin and cytosolic calcium
Author: Adkins, C.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2000
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Inositol triphosphate (IP3) receptors, are commonly responsible for release of Ca2+ from intracellular stores. IP3 binding to type 1, but not type 3, IP3 receptors is inhibited by calmodulin in a Ca2+-independent fashion. Using HSAB-calmodulin to photoaffinity label GST-fusion proteins representing different sequences of the type 1 IP3 receptor, I identified a region that binds calmodulin in both the presence and absence of Ca2+. This region contains a residue (Ser1589) that is phosphorylated by protein kinase A, but protein kinase A-catalysed phosphorylation of purified type 1 IP3 receptors was unaffected by calmodulin in either the presence or absence of Ca2+. I also demonstrated that IP3-evoked Ca2+ release from cerebellar microsomes and cell types that express predominantly type 1, 2 or 3 IP3 receptors, is similarly susceptible to inhibition by calmodulin. In SH-SY5Y cells, which express largely type 1 IP3 receptors, calmodulin inhibited IP3-evoked Ca2+ mobilization only in the presence of Ca2+. This effect of calmodulin did not result from enhanced metabolism of IP3 since calmodulin also reduced the sensitivity of Ca2+ stores to adenophostin A, a non-metabolizable agonist of IP3 receptors. Thus, in contrast to the inhibition of IP3 binding by calmodulin, inhibition of IP3-evoked Ca2+-release occurs only in the presence of Ca2+ and appears to affect all three subtypes of IP3 receptor. Calmodulin also interacts with type 1 IP3 receptors in the absence of Ca2+, but the effects of this interaction on IP3 receptor function remain to be determined.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available