Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms.

The recent proliferation of published TRP channel structures provides a foundation for understanding the diverse functional properties of this important family of ion channel proteins. To facilitate mechanistic investigations, we constructed a structure-based alignment of the transmembrane domains of 120 TRP channel structures. Comparison of structures determined in the absence or presence of activating stimuli reveals similar constrictions in the central ion permeation pathway near the intracellular end of the S6 helices, pointing to a conserved cytoplasmic gate and suggesting that most available structures represent non-conducting states.

The ion selectivity filter is not an activation gate in TRPV1-3 channels.

Activation of TRPV1 channels in sensory neurons results in opening of a cation permeation pathway that triggers the sensation of pain. Opening of TRPV1 has been proposed to involve two gates that appear to prevent ion permeation in the absence of activators: the ion selectivity filter on the external side of the pore and the S6 helices that line the cytosolic half of the pore. Here we measured the access of thiol-reactive ions across the selectivity filters in rodent TRPV1-3 channels.

C-terminal α-synuclein truncations are linked to cysteine cathepsin activity in Parkinson's disease.

A pathological feature of Parkinson's disease (PD) is Lewy bodies (LBs) composed of α-synuclein (α-syn) amyloid fibrils. α-Syn is a 140 amino acids-long protein, but truncated α-syn is enriched in LBs. The proteolytic processes that generate these truncations are not well-understood.

Pupil dilation dynamics track attention to high-level information.

It has long been thought that the eyes index the inner workings of the mind. Consistent with this intuition, empirical research has demonstrated that pupils dilate as a consequence of attentional effort. Recently, Smallwood et al.