9.B.16 The Ductin Channel (Ductin) Family

Ductin is believed to be a highly conserved multifunctional protein serving as 1) the subunit c or proteolipid component of eukaryotic vacuolar and archaeal H -translocating ATPases (TC #3.A.2), 2) the channel-forming protein component of a form of gap junction in metazoan animals (TC #1.A.24), and 3) a putative neurotransmitter release channel, the ''''Mediatophore complex,'''' in synaptic vesicles of animals. Ductin consists of a four transmembrane helix bundle and arose by intragenic duplication of a 2 TMS-encoding genetic unit equivalent to the gene encoding the c-subunits of F-type ATPases (TC #3.A.2). Ductin complexes can transport molecules as large as acetyl choline and glutamate. The ductin pore in V-type ATPases may not provide the pathway for the transport of protons and has been suggested to instead accomodate the polypeptide chains of the stalk. Yeast (S. cerevisiae) contains three ductin paralogues, VMA11, TFP3 and PPA1.

Ca²⁺-dependent acetylcholine release in: i) proteoliposomes, ii) Xenopus oocytes, and iii) release-deficient cell lines is dependent on the expression of the mediatophore, a protein isolated from the plasma membrane of cholinergic nerve terminals of the Torpedo electric organ. The role of the mediatophore in quantal acetylcholine release, its possible involvement in morphological changes affecting presynaptic membrane during the release, and its interactions with others proteins of the cholinergic nerve terminal has been discussed (Bloc et al. 2000). 

Immunological stimulation of T cells by phytohemagglutinin (PHA) enhances the synthesis and release of acetylcholine (ACh). Mediatophore, a homooligomer of a 16-kDa subunit homologous to the proteolipid subunit c of vacuolar H⁺-ATPase mediates ACh release from T cells (Tomina and Takahata 2012). Mediatophore protein is present in the cytoplasm and on the plasma membrane of T cells. Mediatophore gene expression is up-regulated by immunological T cell activation by PHA, and anti-mediatophore small interference RNA down-regulated mediatophore gene expression, significantly reducing ACh release. Thus, T cells express mediatophore, which then plays a key role in mediating ACh release, and mediatophore expression is regulated by immunological stimulation.  Mediatophore, identical to the c-subunit in V-type ATPases, ATP6V0C, also mediates dopamine release from nerve terminals in the striatum of DA neurons (Jin et al. 2012).

Reversible binding of divalent cations to Ductin protein assemblies provides a possible new regulatory mechanism of membrane traffic processes (Sebők-Nagy et al. 2023).  Ductins comprise a family of homologous and structurally similar membrane proteins with 2 or 4 TMSs. The active forms of ductins are membranous ring- or star-shaped oligomeric assemblies, and they provide various pore, channel, gap-junction functions, and they may assist in membrane fusion processes - and also serve as the rotor c-ring domain of V- and F-ATPases. All functions of the Ductins have been reported to be sensitive to the presence of certain divalent metal cations, Me²⁺, most frequently Cu²⁺ or Ca²⁺ for most of the better known members of the family. Possibly certain divalent cations structurally modulate the various functions of Ductin assemblies via affecting their stability by reversible non-covalent binding to them. A fine control of the stability of the assembly ranging from separated monomers through a loosely/weakly to tightly/strongly assembled ring might render precise regulation of Ductin functions possible (Sebők-Nagy et al. 2023). The possible role of direct binding of Me²⁺ to the c-ring subunit of active ATP hydrolase in autophagy and the mechanism of Ca²⁺-dependent formation of the mitochondrial permeability transition pore are also possibilities.

The generalized transport reaction proposed for ductin or mediatophore is:

Small molecules (cytoplasm) small molecules (out or cytoplasm of an adjacent cell)

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