Revelation of an enigmatic signaling machinery—First insights into the mammalian TRPC architecture

Highlights

• Transient receptor potential canonical (TRPC) channel structures are discussed.

• Information from cryo-EM analysis and previous homology modeling are compared.

• Future directions of TRPC resarch are highlighted.

Abstract

Canonical TRP channels (TRPCs) are a particularly enigmatic family of signaling molecules with multimodal sensing features, being involved in a wide range of biological functions. Until very recently, the main hurdle towards comprehensive mechanistic understanding of TRPC signaling has been the lack of structural information. This has changed early this year by several reports on TRPC architectures resolved by single particle cryo-EM analysis. These studies confirmed recently elaborated concepts on TRPC structure-function relations, and unveiled unanticipated features and complexity in the TRPC sensing machinery.

Introduction

Initiated by the discovery the trp gene as an essential element of the fruit fly´s visual transduction [1], seven closely related mammalian homologues were identified. They received much attention by their potential role in cellular Ca²⁺ signaling processes linked to the refilling of intracellular Ca²⁺ stores [2]. A hallmark of the TRPC channels is their tight linkage to phospholipase C activity, based on sensitivity to the lipid mediators diacylglycerols (DAGs) and phosphoinositides [3]. Nonetheless, TRPC molecules display considerable promiscuity with respect to the acceptance of activating/modulating stimuli and have been suggested to function as signal integrators and coincidence detectors [4,5]. Altered expression of the channels or a distortion of TRPC signaling signatures have been related to cellular- and tissue dysfunction, including maladaptive remodeling [6] and malignancy [7]. Therapeutic targeting of TRPCs has motivated the development of small molecule inhibitors and activators, which interfere with permeation and/or gating by as yet unclear molecular mechanisms of action. For most TRPC isoforms the current concepts of molecular function feature gating movements in the pore domain that are triggered by protein-protein and protein-lipid interactions in sensor domains [3]. Primary sensing elements in TRPC complexes have so far been explored by structure-guided mutagenesis approaches and were mainly assigned to motifs in the cytosolic domain [3]. Some parts of the permeation and gating structures have so far been convincingly identified by homology modeling and mutagenesis screens [[8], [9], [10]]. Yet, the TRPC gating machinery with its mediator and drug recognition sites remained enigmatic until very recently. This year several single particle cryo-EM studies have provided a first insight into the unique signal transduction/integration machinery of TRPC channels, including the identification of lipid- and drug interaction sites [[11], [12], [13], [14], [15]].