Glucose and GTP-binding protein-coupled receptor cooperatively regulate transient receptor potential-channels to stimulate insulin secretion [Review]

Abstract

Abstract. In pancreatic β-cells, glucose-induced closure of the ATP-sensitive K + (KATP) channel is an initial process triggering glucose-stimulated insulin secretion (GSIS). This KATP-channel dependent pathway has been believed to be a central mechanism for GSIS. However, since the resting membrane potential of cells is determined by the balance of the net result of current amplitudes in outward and inward directions, it must be taken into consideration that not only KATP channel inhibition but also inward current via the basal opening of non-selective cation channels (NSCCs) plays a crucial role in membrane potential regulation. The basal activity of NSCCs is essential to effectively evoke depolarization in concert with KATP channel closure that is dependent on glucose metabolism. The present study summarizes recent findings regarding the roles of NSCCs in GSIS and GTP-binding protein coupled receptor-(GPCR) operated potentiation of GSIS. Key words: GPCR, Pancreatic β-cells, TRP channel, Insulin secretionTHE CONCEPT that glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is initiated by closure of the ATP-sensitive K + (KATP) channel as a result of an increase in the intracellular ATP/ADP ratio induced by glucose metabolism upon elevation of glucose concentration in the blood ( Fig. 1; the triggering pathway), was proposed a long time ago [1][2][3]. Inhibition of the KATP channel is followed by membrane depolarization and activation of voltage-dependent Ca 2+ channels (VDCCs) [4,5]. Opening of the VDCCs brings about firing of action potential, cytosolic Ca 2+ increase and initiation of GSIS [6,7]. The triggering pathway is followed by time-dependent increase in insulin secretion that is potentiated by glucose exposure (the second phase, potentiating pathway or KATP-independent pathway) [3,8] However, closure of the KATP channel alone is not sufficient to induce a shift in the membrane potential towards the threshold level and for the triggering pathway that can activate VDCCs, since membrane potential is theoretically determined by the overall balance of outward and inward currents. Modest background inward currents through opening of nonselective cation channels (NSCCs) are crucial for induction of membrane depolarization following KATP channel closure [9,10]. This idea further suggests that regulation of a class of NSCCs may play an important role in producing effective depolarization of the membrane. Several types of NSCCs have been reported to be expressed in pancreatic β-cells, which, in terms of ion selectivity, are permeable to Na + , K + , and Ca 2+ . In contrast to these ion channels, which have not been well studied, the classic-type ion channels; i.e., the voltage-dependent Na + channel, the voltage-dependent K + channel [11,12], the voltage-dependent Ca 2+ channel [13,14] and the KATP channel have attracted a large amount of interest for a long time, because the first three types of these ion channels play an important role in membrane excitability and the KATP

The Pancreatic β-Cell: The Perfect Redox System

“…The actually measured Vp R is −75 mV [92]. The closure of 100% of the K ATP ensemble [91,[93][94][95] was reported to lead to only an insufficient partial depolarization of the plasma membrane [6,91]. If the other channels did not contribute, the depolarization by the 100%-closed K ATP ensemble would not be sufficient to activate Ca V channels [96].…”

“…As we discuss in detail in the Section 2.3, either ATP plus H 2 O 2 are required for closing K ATP [4] (Figure 1A); or ATP closes K ATP and H 2 O 2 activates the essential synergic channels (Figure 1B), such as NSCCs [5] or Cl − channels [41]. These synergic channels shift the insufficient depolarization produced by the 100%-closed K ATP population towards the depolarization of the plasma membrane over the approximately −50 mV threshold required for the opening of Ca V [6] (Figure 3). In the latter case, there is no requirement for K ATP to be redox-regulated, but it still could be.…”

“…Interestingly, TRPM2 was also reported to interact with peroxiredoxin 2, from which it can receive the redox signal [114,115]. Additionally, Ca 2+ -activated TRPM4 and TRPM5 channels, heatactivated TRPV1 (capsaicin receptor), and TRPV2 or TRPV4 belong to the important group of NSCCs expressed in β-cells [6]. Among them, the transient receptor potential canonical (TRPC) member 3 (TRPC3) channel was suggested to induce the inward shift in Vp upon the activation of the GPR40 receptor [116].…”

“…The inability of the closure of the entire K ATP ensemble to reach the threshold depolarization of the plasma membrane for opening voltage-gated Ca 2+ channels (Ca V ) [6] is discussed in this review as the key element for understanding the mechanism of GSIS. Thus synergy is required with the other channels.…”

Endogenous α2A-Adrenoceptor–Operated Sympathoadrenergic Tones Attenuate Insulin Secretion via cAMP/TRPM2 Signaling

“…During the process of glucose-stimulated insulin secretion in b-cells, opening of the background inward current through nonselective cation channels (NSCCs) might facilitate depolarization after glucose metabolisminduced closure of the ATP-sensitive K + (K ATP ) channels (9)(10)(11)(12)(13). We previously reported that the transient receptor potential melastatin 2 (TRPM2) channel, a type of NSCC, in b-cells plays an essential role in glucose-induced and incretin-potentiated insulin secretion (9).…”