Calcium Channels in Postnatal Development of Rat Pancreatic Beta Cells and Their Role in Insulin Secretion

Abstract

Pancreatic beta cells during the first month of development acquire functional maturity, allowing them to respond to variations in extracellular glucose concentration by secreting insulin. Changes in ionic channel activity are important for this maturation. Within the voltage-gated calcium channels (VGCC), the most studied channels are high-voltage-activated (HVA), principally L-type; while low-voltage-activated (LVA) channels have been poorly studied in native beta cells. We analyzed the changes in the expression and activity of VGCC during the postnatal development in rat beta cells. We observed that the percentage of detection of T-type current increased with the stage of development. T-type calcium current density in adult cells was higher than in neonatal and P20 beta cells. Mean HVA current density also increased with age. Calcium current behavior in P20 beta cells was heterogeneous; almost half of the cells had HVA current densities higher than the adult cells, and this was independent of the presence of T-type current. We detected the presence of α1G, α1H, and α1I subunits of LVA channels at all ages. The Cav 3.1 subunit (α1G) was the most expressed. T-type channel blockers mibefradil and TTA-A2 significantly inhibited insulin secretion at 5.6 mM glucose, which suggests a physiological role for T-type channels at basal glucose conditions. Both, nifedipine and TTA-A2, drastically decreased the beta-cell subpopulation that secretes more insulin, in both basal and stimulating glucose conditions. We conclude that changes in expression and activity of VGCC during the development play an important role in physiological maturation of beta cells.

Identification of a molecular gating determinant within the carboxy terminal region of Cav3.3 T-type channels

“…In the brain, Ca v 3.3 channels are highly expressed in the olfactory bulb, cortex, midbrain/diencephalon, and in the cerebellum, and to a lesser extent in the hippocampus and pons/medulla [5–7]. In addition, Ca v 3.3 channels were documented in rat pancreatic beta cells [8], human spermatogenic cells [9], and in interstitial cells of Cajal in rat bladder [10].…”

Enhanced expression of β cell Ca V 3.1 channels impairs insulin release and glucose homeostasis

“…Ca V 3.1 channels exist primarily for mediating Ca 2+ influx into the cytosolic compartment to participate in the formation of [Ca 2+ ] i dynamics that regulates glucose-stimulated insulin secretion and maintains β cell specificity (1,(5)(6)(7). This prompted us to examine whether Ad-EGFP-Ca V 3.1 transduction altered [Ca 2+ ] i dynamics, leading to impaired glucose-stimulated insulin secretion.…”

“…M ultiple types of voltage-gated calcium (Ca V ) channels, including Ca V 3.1, operate in the pancreatic β cell mediating Ca 2+ influx in response to membrane depolarization evoked by increased blood glucose (1)(2)(3)(4)(5)(6)(7). Ca 2+ influx through all types of Ca V channels and Ca 2+ mobilization mediated by intracellular Ca 2+ -release channels in the β cell regulate glucose-stimulated insulin secretion (1,(5)(6)(7)(8). In this context, β cell Ca V 1 channels serve as a predominant player compared to other types of β cell Ca V channels due to an optimal elevation in cytosolic free Ca 2+ concentration ([Ca 2+ ] i ) within exocytotic sites (1,(5)(6)(7).…”

“…Ca 2+ influx through all types of Ca V channels and Ca 2+ mobilization mediated by intracellular Ca 2+ -release channels in the β cell regulate glucose-stimulated insulin secretion (1,(5)(6)(7)(8). In this context, β cell Ca V 1 channels serve as a predominant player compared to other types of β cell Ca V channels due to an optimal elevation in cytosolic free Ca 2+ concentration ([Ca 2+ ] i ) within exocytotic sites (1,(5)(6)(7). This optimally elevated [Ca 2+ ] i allosterically initiates direct interactions between exocytotic proteins such as VAMP-2, synaptotagmins III and VII in the insulin granule membrane, and syntaxin 1A and SNAP-25 in the plasma membrane (5)(6)(7)9).…”

The association of calcium channel blockers with β‐cell function in type 2 diabetic patients: A cross‐sectional study

“…Apart from RAAS system, calcium channels are expressed on β‐cell membrane. They regulate cell maturation during development and insulin secretion in response to extracellular glucose concentrations . Moreover, mitochondrial Ca 2+ transiently modulates oxidative metabolism within β cells .…”