Phospholipase C-γ: diverse roles in receptor-mediated calcium signaling

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Ca2+ is a universal signal: the dynamic changes in its release and entry trigger a plethora of cellular responses. Central to this schema are members of the phospholipase C (PLC) superfamily, which relay information from the activated receptor to downstream signal cascades by production of second-messenger molecules. Recent studies reveal that, in addition to its enzymatic activity, PLC-γ regulates Ca2+ entry via the formation of an intermolecular lipid-binding domain with canonical transient receptor potential 3 (TRPC3) ion channels. This complex, in turn, controls TRPC3 trafficking and cell-surface expression. Thus, TRPC3 ion channels are functionally linked to both lipase-dependent and -independent activities of PLC-γ. Understanding the underlying molecular mechanisms that regulate this complex will probably clarify the processes of receptor-activated Ca2+ entry.

Section snippets

The logic of calcium signaling

Ca2+ is a universal cellular messenger and is precisely controlled in all cell types. This is reflected by its large electro–chemical gradient maintained within the cell [1]. Whereas the extracellular Ca2+ environment of cells is 1–2 mM, the cytosol is meticulously controlled in the 100–200-nM Ca2+ range under resting conditions, providing a 10 000-fold gradient across the plasma membrane (PM). Ca2+ levels in the endoplasmic reticulum (ER) resemble those of the extracellular environment, ∼1 mM.

PLC-γ and Ca2+ entry

Functionally, PLC-γ can enhance receptor-mediated ion flux of exogenous and endogenous Ca2+-entry channels independently of its lipase activity 15, 19, 24 (Table 1). PLC-γ can also influence store-operated Ca2+-entry modes 15, 19, 34, 35, an effect that seems to be linked to a secondary Ca2+-dependent rise in PLC-γ2 mediated Ins(1,4,5)P3 production [15]. A gain-of-function PLC-γ2 Δ993G mutant, identified by N-ethyl-N-nitrosourea (ENU) mutagenesis in mouse [34], leads to hyper-reactive Ca2+

PLC-γ and TRP channels

TRP channels are receptor-operated Ca2+-entry channels that are homologous to the Drosophila transient receptor potential channels that mediate phototransduction in the eye [36]. Members of this protein superfamily, which consist of canonical TRP, vanilloid TRP (TRPV), melastatin TRP (TRPM), mucolipidin TRP (TRPML) and polycystin TRP channels (PKD) are widely expressed, receive diverse physiological inputs, and are functionally linked to various disease phenotypes. For example, TRPV and TRPM

Intermolecular PH-like domain

Phosphatidylinositols are key regulators of protein trafficking. Modulation of PtdIns(4,5)P2 levels can affect both exocytic and endocytotic pathways 55, 56. An increasing body of literature supports the direct modulation of ion channels by lipids; however, most ion channels do not contain known lipid-binding motifs 24, 45, 57, 58. Because PLC-γ binds to TRPC3 via its partial, PH-c domain, we propose a model whereby PLC-γ and TRPC3 form an intermolecular PH-like domain [24]. We have developed a

PLC-γ and trafficking

It has been shown that vesicle-associated membrane protein 2 (VAMP2) [49], PI3K, the Rho GTPase Rac1 and phosphatidylinositol 4-phosphate 5-kinase [47] regulate other TRPC channels at the level of rapid vesicular insertion of TRP, therefore, this might be the case for regulation of TRPC3 by PLC-γ (Figure 4). PLC-γ, as both lipase and GEF, could be a key regulatory component within this lipid- and GTP-dependent complex.

Alternatively, or in addition to exocytosis, PLC-γ could influence the

Conformational switch

The ability of PLC-γ to switch between lipase-dependent and lipase-independent activity implies that a conformational shift differentiates these functions (Figure 5). The catalytic-domain X and Y boxes, which are separated in PLC-γ, might reunite in the lipase-active conformation to facilitate reconstitution of the split PH domain fragments 19, 24, 34, 59. In the lipase-independent conformation, the X and Y boxes might separate, enabling the intervening interaction domains (SH2 and SH3–GEF) and

PLC family: evolution and GDDA

Evolutionarily, PLCs are conserved in plants, fungi and animals, and most animal genomes encode multiple PLC paralogous proteins. In metazoa, the PLC family of proteins can be divided into two major evolutionary groups: group I consists of the -δ, -ζ and -like sequences, and group II consists of the -ε, -β, -γ and fungi sequences (Figure 6a). The phylogenetic grouping, together with the presence or absence of the different domains, suggests that the PLC molecule of the common ancestor of all

Concluding remarks

Evidence for multiple PLC-γ functions is mounting. PLC-γ generates the second-messenger molecules Ins(1,4,5)P3 and DAG, both of which are involved in receptor-mediated Ca2+ signaling. The recent finding that PLC-γ also regulates the cell-surface expression of TRPC channels via the formation of an inter-molecular non-canonical lipid-binding domain indeed demonstrates the multiplicity of PLC-γ function. Furthermore, taking into account that motifs for non-canonical lipid-binding domains are

Acknowledgements

This research was supported by US Public Health Service Grants MH-18501 and DA-000266, Research Scientist Award DA-00074 (S.H.S.) and National Institutes of Health Grant HL55426 (D.L.G.). We acknowledge Dimitra Chalkia and Kyung De Ko for their role in developing the GDDA and thank M. Mathers III and A. Dre for useful discussion.

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      TRPC3 can also be activated independently of PLC stimulation via Gαi/o-evoked and Rho GTPase activation of phospholipase D (PLD) which releases phosphatidic acid and choline, and may subsequently produce lysophosphatidic acid and DAG (Glitsch, 2010; Kwan et al., 2009; Large, Saleh, & Albert, 2009). Like most TRP channels, TRPC3 activation can occur via PLC-γ downstream from cytokine and tyrosine kinase receptors, and this activation may proceed by two mechanisms, as lipase-dependent hydrolysis of phosphoinositides to generate DAG and inositol 1,4,5-trisphosphate (IP3), and via lipase-independent regulation of trafficking, membrane retention and hence surface expression (Patterson, van Rossum, Nikolaidis, Gill, & Snyder, 2005; Patterson et al., 2002; van Rossum et al., 2005). Recent evidence for the involvement of TRPC3 in bone-derived neurotrophic factor (BDNF)-mediated modulation of inflammatory responses in microglia (Mizoguchi et al., 2014) and in the alleviation of hypoxia-induced apoptosis in cardiomyocytes (Hang et al., 2015) provides support for the involvement of the latter mechanism in TRPC3 activation.

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    Authors contributed equally to this work.

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