Derived (Mutated)–Types of TRPV6 Channels Elicit Greater Ca2+ Influx Into the Cells Than Ancestral-Types of TRPV6: Evidence From Xenopus Oocytes and Mammalian Cell Expression System

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The frequency of the allele containing three derived nonsynonymous SNPs (157C, 378M, 681M) of the gene encoding calcium permeable TRPV6 channels expressed in the intestine has been increased by positive selection in non-African populations. To understand the nature of these SNPs, we compared the properties of Ca2+ influx of ancestral (in African populations) and derived-TRPV6 (in non-African populations) channels with electrophysiological, Ca2+-imaging, and morphological methods using both the Xenopus oocyte and mammalian cell expression systems. Functional electrophysiological and Ca2+-imaging analyses indicated that the derived-TRPV6 elicited more Ca2+ influx than the ancestral one in TRPV6-expressing cells where both channels were equally expressed in the cells. Ca2+-inactivation properties in the ancestral- and derived-TRPV6 were almost the same. Furthermore, fluorescence resonance energy transfer (FRET) analysis showed that both channels have similar multimeric formation properties, suggesting that derived-TRPV6 itself could cause higher Ca2+ influx. These findings suggest that populations having derived-TRPV6 in non-African areas may absorb higher Ca2+ from the intestine than ancestral-TRPV6 in the African area.