Dopamine D Agonists: First Potential Treatment for Late-Stage Parkinson's Disease.

Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson's disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. We explored if a D dopamine agonist would have efficacy in LsPD using a double-blind placebo-controlled crossover phase Ia/b study comparing the D agonist PF-06412562 to levodopa/carbidopa in six LsPD patients.

Pore properties of Orai1 calcium channel dimers and their activation by the STIM1 ER calcium sensor.

Store-operated Ca entry signals are mediated by plasma membrane Orai channels activated through intermembrane coupling with Ca-sensing STIM proteins in the endoplasmic reticulum (ER). The nature of this elaborate Orai-gating mechanism has remained enigmatic. Based on the Orai structure, mammalian Orai1 channels are hexamers comprising three dimeric subunit pairs.

Cross-linking of Orai1 channels by STIM proteins.

The transmembrane docking of endoplasmic reticulum (ER) Ca-sensing STIM proteins with plasma membrane (PM) Orai Ca channels is a critical but poorly understood step in Ca signal generation. STIM1 protein dimers unfold to expose a discrete STIM-Orai activating region (SOAR1) that tethers and activates Orai1 channels within discrete ER-PM junctions. We reveal that each monomer within the SOAR dimer interacts independently with single Orai1 subunits to mediate cross-linking between Orai1 channels.

The STIM-Orai Pathway: Conformational Coupling Between STIM and Orai in the Activation of Store-Operated Ca Entry.

Store-operated Ca entry fulfills a crucial role in controlling Ca signals in almost all cells. The Ca-sensing stromal interaction molecule (STIM) proteins in the endoplasmic reticulum (ER) undergo complex conformational changes in response to depleted ER luminal Ca, allowing them to unfold and become trapped in ER-plasma membrane (PM) junctions. Dimers of STIM proteins trap and gate the plasma membrane Orai Ca channels within these junctions to generate discrete zones of high Ca and regulate sensitive Ca-dependent intracellular signaling pathways.

The STIM-Orai coupling interface and gating of the Orai1 channel.

In virtually all cells, store-operated Ca entry signals are vital in controlling a spectrum of functions. The signals are mediated by STIM proteins in the ER and Orai channels in the PM which undergo a dynamic coupling process within discrete ER-PM junctional regions. This coupling is initiated by depletion of ER stored Ca triggering STIM proteins to undergo an intricate activation process.