Novel Spliced Variants of Large-Conductance Ca2+-Activated K+-Channel β2-Subunit in Human and Rodent Pancreas

Abstract

Abstract. Large-conductance Ca 2+ -activated K + (BK) channel regulates action potential firing in pancreatic β-cells. We cloned novel spliced variants of the BK-channel β 2 -subunit (BKβ2b), which consisted of 36 amino acids including the N-terminal in the original human BKβ2 (BKβ2a), from human and rodent pancreas. Real-time PCR analysis showed the abundant expression of BKβ2b transcripts in human and rodent pancreas and also in the RINm5f insulinoma cell line. In addition, up-regulation of both BK-channel α-subunit (BKα) and BKβ2b transcripts was observed in pancreas tissues from diabetes mellitus patients. In HEK293 cells co-expressing BKα and BKβ2b, the inactivation of BK-channel currents, which is typical for BKα + BKβ2a, was not observed, and electrophysiological and pharmacological properties of BKα + BKβ2b were almost identical to those of BKα alone. In HEK293 cells stably expressing BKα, the transient co-expression of yellow fluorescence protein (YFP)-tagged BKβ2a proteins resulted in their distribution along the cell membrane. In contrast, the co-expression of YFP-tagged BKβ2b with BKα showed diffusely distributed fluorescence signals throughout the cell body. Taken together, the predominant splicing of BKβ2b versus that of BKβ2a presumably enhances the contribution of BK channels to membrane potential and may possibly be a factor modulating insulin secretion in a suppressive manner in pancreatic β-cells.

Definitive Endoderm Formation from Plucked Human Hair-Derived Induced Pluripotent Stem Cells and SK Channel Regulation

“…SK4 can be detected in inflammatory cell-rich, surface-rich, and secretory tissues such as the pancreas [63]. In the pancreas, for example, SK4 regulates glucose homeostasis and enzyme secretion of acinar cells [64, 65]. Moreover, SKCas are overexpressed in a variety of cancers, including pancreatic cancer [20] and, for example, SK3 was shown to be involved in cancer cell migration [66].…”

Reciprocal Relationship between Ca²⁺ Signaling and Ca²⁺-Gated Ion Channels as a Potential Target for Drug Discovery

“…5,129) BK channelopathy due to gain-and loss-offunction mutations has been identified in 16 mutations, which mainly result in neurological symptoms, such as epilepsy, ataxia, mental retardation, and chronic pain. 130) A large number of splice variants of α-subunits, 61,126,131) variants of β1-β4, 132) and newly identified γ-subunits 133) have contributed to the diversity of the physiological properties of BK channels. 134,135) The BK channel is a factor in the pathogenesis of CNS diseases, including epilepsy.…”

A BK (Slo1) channel journey from molecule to physiology

“…In humans, alterations in BK channels are known to be important in the pathophysiology of hypertension, 204,205 asthma, 206 diabetes, and vascular insulin secretion, 123,207 epilepsy, [208][209][210] and cancer. 211,212 In this section we will briefly discuss some of these findings that link BK channels with the diseases in which they play a major role.…”

“…222 Splice variants of β2 subunits (i.e., β2a and β2b) have been observed to be expressed in the pancreas in experimental models as well as in patients with diabetes. 123 The predominant splice variant is β2b, and the functional characteristics of α subunit and β2b complexes expressed in heterologous systems are almost identical to those of the α subunit alone, lacking inactivation. This fact may explain alterations of insulin secretion by pancreas islets during diabetes.…”