Ca2+-Activated Chloride Channels and Phospholipid Scramblases

The functional characterization of the TMEM16 protein family unexpectedly brought
together two different research fields in membrane biology: anion channel and membrane
lipid organization. Almost 40 years ago, Miledi described for the first time the presence of
ion channels allowing the permeation of chloride ions activated by intracellular Ca2+ on
the plasma membrane of Xenopus laevis oocytes [ 1]. In the same year, the investigation of
platelets activation revealed the presence of Ca2+-dependent mechanisms mediating the
exposure phosphatidylserine on the outer leaflet of the membrane dissipating the lipid
asymmetry [2, 3]. Later, the term "scramblase" was proposed for the proteins mediating
this process.
Further investigations shows that both Ca2+-activated Cl ? channels (CaCCs) and
scramblases are expressed in various tissues playing important physiological roles. In
particular, CaCCs are involved in the secretion of different types of exocrine glands; regulate
the contraction of vascular smooth muscle cells relevant to the modulation of blood pressure;
control the chloride secretion in different epithelia functionally interacting with the cystic
fibrosis transmembrane regulator (CFTR); and modulate the neuronal firing activity and
the sensory transduction in olfactory systems [ 4, 5]. Similarly, phospholipid scramblase has
a pivotal role in the blood coagulation and in the removal of apoptotic cells [6].
In 2008 and 2010, the molecular identities of Ca2+-activated Cl ? channels and phospho-
lipid scramblases were discovered [ 7- 10]. Different expression cloning approaches revealed
that two members of the "transmembrane proteins with unknown function 16", TMEM16,
encode for CaCCs, and at least one member of the same family forms the phospholipid
scramblase [ 7 -10 ]. These seminal discoveries opened the possibility of investigation at the
molecular level of CaCCs and phospholipid scramblases.
Today, we know that in mammals, the TMEM16 family, also known as the anoc-
tamin family, is composed of 10 members with different functions and physiological roles
(Figure 1) [11,12]. TMEM16A and B are classical CaCCs expressed mainly in epithelial and
neuronal cell types, respectively [ 13]. TMEME16C, D, E, F, G, J and K are phospholipid
scramblases [ 14 - 16]. Moreover, TMEM16D, E and F are also Ca2+-activated ion chan-
nels [17-19 ], and TMEM16J is an ion channel activated by the cAMP/PKA pathway [ 20 ].
Finally, TMEM16C modulates the activity of Na+-activated K+ channels [21]. Many of the
TMEM16 proteins are involved in human diseases. In particular, mutations in TMEM16C
cause craniocervical dystonia [22], TMEM16E cause gnatodiaphyseal dysplasia [23 ] and
muscular dystrophy [24 ], mutations in TMEM16F are responsible for Scott syndrome [ 16],
while a form of spinocerebellar ataxia is due to mutations in TMEM16K [ 25]. Moreover,
many data show that TMEM16 is involved in cell proliferation and is overexpressed in
several types of cancer [26 ]. TMEM16A can also contributes to pathogenesis of cystic
fibrosis by a complex functional interplay with CFTR [ 27 ]. Finally, TMEM16E, G and J are
also involved in several types of cancer [28-31].
In the Special Issue of International Journal of Molecular Sciences "Ca2+-Activated Chlo-
ride Channels and Phospholipid Scramblases", we edited several papers bringing new
light on the function of this interesting protein family.
Choi et al. reported that TMEM16A could be involved in psoriasis pathogenesis [32].
Psoriasis, affecting about 2% of the human population, is a multifactorial skin disease
causing erythematous plaques, papules and pruritus [ 33]. Psoriatic skin shows both
hyperplasia of the epidermis caused by over-proliferation of keratinocytes, and alteration
in the proinflammatory response [3