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Origin of slow and fast oscillations of Ca²⁺ in mouse pancreatic islets

Yi-Jia Liu, Anders Tengholm, Eva Grapengiesser, Bo Hellman and Erik Gylfe

1. Pancreatic islets exposed to 11 mM glucose exhibited complex variations of cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i) with slow (0·3-0·9 min^-1) or fast (2-7 min^-1) oscillations or with a mixed pattern.

2. Using digital imaging and confocal microscopy we demonstrated that the mixed pattern with slow and superimposed fast oscillations was due to separate cell populations with the respective responses.

3. In islets with mixed [Ca²⁺]_i oscillations, exposure to the sarcoplasmic-endoplasmic reticulum Ca²⁺-ATPase inhibitors thapsigargin or 2,5-di-tert-butylhydroquinone (DTBHQ) resulted in a selective disappearance of the fast pattern and amplification of the slow pattern.

4. In addition, the protein kinase A inhibitor R_P-cyclic adenosine 3',5'-monophosphorothioate sodium salt transformed the mixed [Ca²⁺]_i oscillations into slow oscillations with larger amplitude.

5. Islets exhibiting only slow oscillations reacted to low concentrations of glucagon with induction of the fast or the mixed pattern. In this case the fast oscillations were also counteracted by DTBHQ.

6. The spontaneously occurring fast oscillations seemed to require the presence of cAMP-elevating glucagon, since they were more common in large islets and suppressed during culture.

7. Image analysis revealed [Ca²⁺]_i spikes occurring irregularly in time and space within an islet. These spikes were preferentially observed together with fast [Ca²⁺]_i oscillations, and they became more common after exposure to glucagon.

8. Both the slow and fast oscillations of [Ca²⁺]_i in pancreatic islets rely on periodic entry of Ca²⁺. However, the fast oscillations also depend in some way on paracrine factors promoting mobilization of Ca²⁺ from intracellular stores. It is proposed that such a mobilization in different cells within a tightly coupled islet syncytium generates spikes which co-ordinate the regular bursts of action potentials underlying the fast oscillations.

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