Budelli, G. | Search bioRxiv

bioRxiv2022

Heat and humidity sensors that alert mosquitoes to nearby human hosts

Mosquito-borne diseases sicken >500,000,000 people annually, killing >500,0001. Mosquito host-seeking is guided by multiple host-associated cues, which combine to drive blood feeding in a manner that remains poorly understood2,3. While heat is a powerful mosquito attractant, recent studies indicate that disruption of heat seeking has little impact on host detection by the malaria vector Anopheles gambiae4, suggesting other cues act alongside heat in the complex sensory environment of a human host. Here we show mosquitoes require Ir93a (an Ionotropic Receptor5) to maintain attraction to a human host and feed on warmed blood. Using Ir93a, we uncover the previously uncharacterized mosquito hygrosensory system, and show Ir93a is required for humidity detection by humidity sensors (hygrosensors) as well as temperature detection by thermosensors, and for attraction to each stimulus. These findings indicate that hygrosensation and thermosensation function in parallel, driving host proximity detection in response to the overlapping heat and humidity gradients humans produce6,7. These host cue sensors appear to have arisen by co-opting existing sensors of physical cues rather than de novo, as Ir93a-dependent thermo- and hygro-sensors support physiological homeostasis in non-blood-feeding insects8-11. While Ir93a is conserved among arthropods, reliance on heat and humidity evolved independently in multiple blood-feeding lineages, suggesting multiple, vector-specific implementations of this common host-seeking strategy.

neuroscience↗

bioRxiv2020

Coupling of Ca2+ and voltage activation in BK channels through the αB helix/voltage sensor interface

Large conductance Ca2+ and voltage activated K+ (BK) channels control membrane excitability in many cell types. BK channels are tetrameric. Each subunit is comprised of a voltage sensor domain (VSD), a central pore gate domain, and a large cytoplasmic domain (CTD) that contains the Ca2+ sensors. While it is known that BK channels are activated by voltage and Ca2+, and that voltage and Ca2+ activations interact, less is known about the mechanisms involved. We now explore mechanism by examining the gating contribution of an interface formed between the VSDs and the B helices located at the top of the CTDs. Proline mutations in the B helix greatly decreased voltage activation while having negligible effects on gating currents. Analysis with the HCA model indicated a decreased coupling between voltage sensors and pore gate. Proline mutations decreased Ca2+ activation for both Ca2+ bowl and RCK1 Ca2+ sites, suggesting that both high affinity Ca2+ sites transduce their effect, at least in part, through the B helix. Mg2+ activation was also decreased. The crystal structure of the CTD with proline mutation L390P showed a flattening of the first helical turn in the B helix compared to WT, without other notable differences in the CTD, indicating structural change from the mutation was confined to the B helix. These findings indicate that an intact B helix/VSD interface is required for effective coupling of Ca2+ binding and voltage depolarization to pore opening, and that shared Ca2+ and voltage transduction pathways involving the B helix may be involved. SignificanceLarge conductance BK (Slo1) K+ channels are activated by voltage, Ca2+, and Mg2+ to modulate membrane excitability in neurons, muscle, and other cells. BK channels are of modular design, with pore-gate and voltage sensors as transmembrane domains and a large cytoplasmic domain CTD containing the Ca2+ sensors. Previous observations suggest that voltage and Ca2+ sensors interact, but less is known about this interaction and its involvement in the gating process. We show that a previously identified structural interface between the CTD and voltage sensors is required for effective activation by both voltage and Ca2+, suggesting that these processes may share common allosteric activation pathways. Such knowledge should help explain disease processes associated with BK channel dysfunction.

neuroscience↗