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2015 ; 4
(1
): 4-22
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Two-Pore Channels: Lessons from Mutant Mouse Models
#MMPMID27330869
Ruas M
; Galione A
; Parrington J
Messenger (Los Angel)
2015[Jun]; 4
(1
): 4-22
PMID27330869
show ga
Recent interest in two-pore channels (TPCs) has resulted in a variety of studies
dealing with the functional role and mechanism of action of these endo-lysosomal
proteins in diverse physiological processes. With the availability of mouse lines
harbouring mutant alleles for Tpcnl and/or Tpcn2 genes, several studies have made
use of them to validate, consolidate and discover new roles for these channels
not only at the cellular level but, importantly, also at the level of the whole
organism. The different mutant mouse lines that have been used were derived from
distinct genetic manipulation strategies, with the aim of knocking out expression
of TPC proteins. However, the expression of different residual TPC sequences
predicted to occur in these mutant mouse lines, together with the varied degree
to which the effects on Tpcn expression have been studied, makes it important to
assess the true knockout status of some of the lines. In this review we summarize
these Tpcn mutant mouse lines with regard to their predicted effect on Tpcn
expression and the extent to which they have been characterized. Additionally, we
discuss how results derived from studies using these Tpcn mutant mouse lines have
consolidated previously proposed roles for TPCs, such as mediators of NAADP
signalling, endo-lysosomal functions, and pancreatic ? cell physiology. We will
also review how they have been instrumental in the assignment of new
physiological roles for these cation channels in processes such as membrane
electrical excitability, neoangiogenesis, viral infection and brown adipose
tissue and heart function, revealing, in some cases, a specific contribution of a
particular TPC isoform.