σ Receptor ligands and imidazoline secretagogues mediate their insulin secretory effects by activating distinct receptor systems in isolated islets

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Abstract

The effects of two potent σ receptor agonists (+)-3-PPP ((R)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine) and DTG (N,N′-di-(o-tolyl)guanidine) on the insulin secretory responses in rat islets of Langerhans were investigated. Both σ receptor ligands were able to potentiate the insulin secretory response of islets incubated at 6 mM glucose, in a dose-dependent manner and were also able to reverse the effects of diazoxide on insulin release. When islets were treated with efaroxan, a well-characterised imidazoline insulin secretagogue, and either (+)-3-PPP or DTG together, there was an unexpected and profound absence of stimulation of insulin release as compared to when islets were incubated with each compound alone. Experiments performed with islets where there was desensitization of DTG/σ receptor or efaroxan/imidazoline binding site mediated responses suggest that at least two distinct receptor systems appear to be involved. The complex interactions of these two classes of drug require further investigation.

Introduction

Imidazoline insulin secretagogues, such as efaroxan and phentolamine, are thought to mediate their effects in the pancreatic β-cell primarily by inducing the closure of ATP-sensitive (KATP) K+ channels (Schulz and Hasselblatt, 1989; Chan and Morgan, 1990; Chan et al., 1991; Chan, 1993; Plant and Henquin, 1990; Dunne, 1991; Jonas et al., 1992). The nature of the binding site responsible for this effect has still not been defined in detail but it appears to be `atypical', in that it is pharmacologically distinct (Chan et al., 1994; Olmos et al., 1994; Zaitsev et al., 1996) from the imidazoline I1 and I2 receptors described in other tissues (Michel and Ernsberger, 1992; Regunathan and Reis, 1996). It is also unclear whether the imidazoline binding site forms part of the KATP channel itself or whether it is located on a separate protein. In this context, accumulating evidence indicates that the imidazoline binding site is not associated with the sulphonylurea receptor (which forms one of the two known subunits of the KATP channel) (Brown et al., 1993; Dunne et al., 1995; Ishida-Takayashi et al., 1996; Rustenbeck et al., 1997) and, as a consequence, it has been argued that the ion-conducting subunit (designated Kir6.2) probably contains the imidazoline binding domain (Proks and Ashcroft, 1997). This suggestion assumes particular significance in view of recent results which have been taken to indicate that a common feature of several ion channels may be the possession of a binding site for σ ligands. Occupation of this site (the phencyclidine (PCP)/σ `receptor') is assumed to result in occlusion of the ion-conducting pore of these channels, causing a reduction in ion flow. Molderings et al. (1996)have shown that some imidazoline drugs can displace the binding of radioligands to σ sites on ion channels and Olmos et al. (1996)have provided evidence for a correlation between the effects of imidazolines on insulin secretion and their affinity for PCP/σ receptors.

Based on such observations, the hypothesis was advanced that the capacity of imidazoline compounds to stimulate insulin secretion may reflect their ability to occupy a PCP/σ binding site on the islet β-cell KATP channel, leading to occlusion of the ion-conducting pore. This would cause a reduction in the rate of K+ efflux promoting membrane depolarisation, gating of voltage-sensitive calcium channels and enhancement of insulin release. However, we have recently presented preliminary evidence suggesting that this hypothesis may be an over-simplification since two compounds which display high affinity for PCP/σ binding sites associated with ion channels (phencyclidine and dizoclipine) are, at best, only weakly effective as insulin secretagogues (Chan et al., 1997).

In the present study, we have extended this work to examine more fully the effects of two further high affinity σ receptor ligands, DTG (N,N′-di-(o-tolyl)guanidine) and (+)-3-PPP ((R)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine hydrochloride), on insulin release from isolated rat islets. Moreover, we have studied the interactions between these compounds and imidazoline drugs to ascertain whether they share a common mechanism of action.

Section snippets

Materials

Collagenase (type XI), (+)-3-PPP ((R)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine hydrochloride) and diazoxide were purchased from Sigma (Poole, Dorset, UK). DTG (N,N′-di-(o-tolyl)guanidine) was purchased from Tocris Cookson (Bristol, UK). Glibenclamide was a gift from SmithKline Beecham Pharmaceuticals (Welwyn, Herts., UK). Efaroxan was a gift from Reckitt and Colman Products (Kingston-upon-Hull, UK). [125I]iodine and anti-bovine insulin antiserum (for radioimmunoassay, RIA) were from ICN

Secretory responses to DTG and 3-PPP

It has been shown previously that the insulin secretagogue activity of imidazolines, including efaroxan, is glucose-dependent. Therefore, in initial studies the effects of DTG and (+)-3-PPP were investigated in islets incubated with increasing concentrations of glucose. Islets responded to increasing glucose (0–20 mM) with the typical sigmoidal dose–response curve (Fig. 1A). The inclusion of each of the σ receptor ligands (100 μM) resulted in a further elevation of the secretory rate at

Discussion

Considerable effort has been invested over the last decade to understand the functional roles of σ receptors and they have now been implicated in a diversity of physiological and pathophysiological processes (reviewed by Walker et al., 1990; Su, 1991). These include control of motor functions, neurotransmitter synthesis and release, regulation of smooth muscle contraction and neurodegeneration. In addition, we now show that certain σ receptor agonists (though not all) can stimulate insulin

Acknowledgements

We thank the Wellcome Trust for their support of this work. SLFC is a Wellcome Trust Career Development Fellow.

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