Priestley,, Tony; (1993) Electrophysiological and radioligand binding characterisation of somatostatin receptors in rat brain and pituitary. Doctoral thesis (Ph.D.), University College London (United Kingdom).

Text Electrophysiological_and_radio.pdf Download (21MB)

Abstract

Somatostatin (SS14) is a tetradecapeptide which is widely distributed throughout the brain and peripheral tissues of mammals. A number of published studies have demonstrated that somatostatin is a member of a family of related peptides and that its many pharmacological effects may be mediated by different receptor subtypes. This thesis describes a series of experiments which sought to further examine the evidence for receptor heterogeneity in the tissues of the laboratory rat. The specific binding of the broad spectrum radiolabelled agonist, [125I]Tyr11-SS14, to membranes of rat cerebral cortex was displaced by unlabelled endogenous somatostatin peptides with high affinity (Ki ~ 1nM), Several short-chain synthetic analogues of somatostatin, seglitide, octreotide and L-363,301, also displaced ligand binding but in a biphasic manner consisting of both high and low affinity components. A fourth analogue, somatuline, had only low affinity for cortical membranes. These results suggested the existence of receptor subtypes with differential affinities for the short-chain, conformationally-constrained analogues. Autoradiographic studies were undertaken in order to map the distribution of analogue-sensitive and -resistant somatostatin binding sites in rat brain. In the LC and pituitary, comparisons of binding-displacement curves suggested a single class of non-interacting sites for which the endogenous peptides and short-chain analogues had similar affinity. In the hippocampus, displacement curves to the analogues were biphasic, suggesting a mixed population of binding sites. Somatuline bound to hippocampal and cortical regions with very low affinity and was approximately 1000-fold selective for the LC/pituitary binding sites. Electrophysiological experiments were performed on several brain regions in vitro and on cells in tissue culture in an attempt to identify functional correlates of the different binding sites. Responses to somatostatin were qualitatively similar regardless of the tissue and consisted of a membrane hyperpolarization which appeared to be the consequence of an increased conductance to potassium ions. The effects of somatostatin peptides were also characterised on the anococcygeus muscle in order to compare central and peripheral receptors. These experiments provided further evidence in support of multiple somatostatin receptor subtypes. Differences in the relative affinities of somatostatin analogues for binding sites in higher brain centres, pituitary and LC suggested that binding site heterogeneity may be more extensive than previously thought.

Download activity - last month

Export as XMLJSONCSV

Download activity - last 12 months

Export as JSONCSVXML

Downloads by country - last 12 months

Export as XMLCSVJSON

Archive Staff Only

View Item