Nir1 constitutively localizes at ER-PM junctions and promotes Nir2 recruitment for PIP2 homeostasis

Homeostatic regulation of plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PIP2) in receptor-stimulated cells is mediated by the lipid transfer protein Nir2. Nir2 is dynamically recruited to endoplasmic reticulum-plasma membrane (ER-PM) junctions to facilitate replenishment of PM PIP2 hydrolyzed during receptor-mediated signaling. However, our knowledge regarding the activation and sustainment of Nir2-mediated replenishment of PM PIP2 is limited. Here, we describe the functions of Nir1 as a positive regulator of Nir2 and PIP2 homeostasis. In contrast to the family proteins Nir2 and Nir3, Nir1 constitutively localizes at ER-PM junctions. Nir1 potentiates Nir2 targeting to ER-PM junctions during receptor-mediated signaling and is required for efficient PM PIP2 replenishment. Live-cell imaging and biochemical analysis reveal that Nir1 interacts with Nir2 via a region between the FFAT motif and the DDHD domain. Combined, results from this study identify Nir1 as an ER-PM junction localized protein that promotes Nir2 recruitment for PIP2 homeostasis.

Music Listening and Homeostatic Regulation: Surviving and Flourishing in a Sonic World

This paper argues for a biological conception of music listening as an evolutionary achievement that is related to a long history of cognitive and affective-emotional functions, which are grounded in basic homeostatic regulation. Starting from the three levels of description, the acoustic description of sounds, the neurological level of processing, and the psychological correlates of neural stimulation, it conceives of listeners as open systems that are in continuous interaction with the sonic world. By monitoring and altering their current state, they can try to stay within the limits of operating set points in the pursuit of a controlled state of dynamic equilibrium, which is fueled by interoceptive and exteroceptive sources of information. Listening, in this homeostatic view, can be adaptive and goal-directed with the aim of maintaining the internal physiology and directing behavior towards conditions that make it possible to thrive by seeking out stimuli that are valued as beneficial and worthy, or by attempting to avoid those that are annoying and harmful. This calls forth the mechanisms of pleasure and reward, the distinction between pleasure and enjoyment, the twin notions of valence and arousal, the affect-related consequences of music listening, the role of affective regulation and visceral reactions to the sounds, and the distinction between adaptive and maladaptive listening.

Homeostatic regulation of axonal Kv1.1 channels accounts for both synaptic and intrinsic modifications in the hippocampal CA3 circuit

Homeostatic plasticity of intrinsic excitability goes hand in hand with homeostatic plasticity of synaptic transmission. However, the mechanisms linking the two forms of homeostatic regulation have not been identified so far. Using electrophysiological, imaging, and immunohistochemical techniques, we show here that blockade of excitatory synaptic receptors for 2 to 3 d induces an up-regulation of both synaptic transmission at CA3–CA3 connections and intrinsic excitability of CA3 pyramidal neurons. Intrinsic plasticity was found to be mediated by a reduction of Kv1.1 channel density at the axon initial segment. In activity-deprived circuits, CA3–CA3 synapses were found to express a high release probability, an insensitivity to dendrotoxin, and a lack of depolarization-induced presynaptic facilitation, indicating a reduction in presynaptic Kv1.1 function. Further support for the down-regulation of axonal Kv1.1 channels in activity-deprived neurons was the broadening of action potentials measured in the axon. We conclude that regulation of the axonal Kv1.1 channel constitutes a major mechanism linking intrinsic excitability and synaptic strength that accounts for the functional synergy existing between homeostatic regulation of intrinsic excitability and synaptic transmission.

Sleep Need, the Key Regulator of Sleep Homeostasis, Is Indicated and Controlled by Phosphorylation of Threonine 221 in Salt Inducible Kinase 3

Sleep need drives sleep and plays a key role in homeostatic regulation of sleep. So far sleep need can only be inferred by animal behaviors and indicated by electroencephalography (EEG). Here we report that threonine 221 (T221) of the salt inducible kinase 3 (SIK3) was important for the catalytic activity and stability of SIK3. T221 phosphorylation in the mouse brain indicates sleep need: more sleep resulting in less phosphorylation and less sleep more phosphorylation during daily sleep/wake cycle and after sleep deprivation (SD). Sleep need was reduced in SIK3 loss of function (LOF) mutants and by T221 mutation to alanine (T221A). Sleep rebound after SD was also decreased in SIK3 LOF and T221A mutant mice. Other kinases such as SIK1 and SIK2 or other sites in SIK3 do not fulfil criteria to be both an indicator and a controller of sleep need. Our results reveal SIK3 T221 phosphorylation as the first and only chemical modification which indicates and controls sleep need.

Perspective Chapter - NMDA Treatments for CNS Disorders

The N-methyl-D-aspartate receptor (NMDAR), a glutamate-gated ion channel, mediates various physiological functions, such as synaptic plasticity, learning, and memory. Any homeostatic dysregulation of NMDAR may cause central nervous system (CNS) disorders, such as Alzheimer’s disease, depression, and schizophrenia. The involvement of NMDA dysfunction promotes advanced research on developing NMDAR pharmaceutics for treating CNS disorders. NMDAR enhancers, by direct or indirect potentiating NMDAR functions, have been used to recover NMDAR functions for treating schizophrenia. Interestingly, NMDAR blockers, by direct or indirect inhibiting NMDAR functions, have also been utilized for CNS disorders, such as Alzheimer’s disease and depression. In this chapter, the current strategy of NMDAR modulation for CNS disorders are elaborated on to discern underlying neurophysiological mechanisms of how homeostatic regulation of NMDAR plays a vital role in the normal and pathological states, respectively.

The Impact of ACE2 Polymorphisms on COVID-19 Disease: Susceptibility, Severity, and Therapy

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has currently spread worldwide, leading to high morbidity and mortality. As the putative receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) is widely distributed in various tissues and organs of the human body. Simultaneously, ACE2 acts as the physiological counterbalance of ACE providing homeostatic regulation of circulating angiotensin II levels. Given that some ACE2 variants are known to cause an increase in the ligand-receptor affinity, their roles in acquisition, progression and severity of COVID-19 disease have aroused widespread concerns. Therefore, we summarized the latest literature and explored how ACE2 variants and epigenetic factors influence an individual’s susceptibility to SARS-CoV-2 infection and disease outcome in aspects of ethnicity, gender and age. Meanwhile, the possible mechanisms for these phenomena were discussed. Notably, recombinant human ACE2 and ACE2-derived peptides may have special benefits for combating SARS-CoV-2 variants and further studies are warranted to confirm their effects in later stages of the disease process. As the uncertainty regarding the severity and transmissibility of disease rises, a more in-depth understanding of the host genetics and functional characteristics of ACE2 variants will not only help explain individual clinical differences of the disease, but also contribute to providing effective measures to develop solutions and manage future outbreaks of SARS-CoV-2.

Chronic caffeine treatment disrupts the circadian rhythm in Drosophila

The circadian clock governs the timing of sleep-wake cycles as well as of other behavioural, physiological and metabolic processes. While the endogenous circadian clock mediates the timing of sleep, homeostatic mechanisms modulate the amount and depth of sleep. Evidence from previous studies showed that caffeine intake promotes wakefulness, whereas adult-stage specific caffeine treatment not only suppresses sleep but also delays the phase of circadian rhythm in Drosophila. In humans, caffeine is consumed on a daily basis and hence it is important to understand the effect of prolonged caffeine intake on circadian and homeostatic regulation of sleep. In the present study we examined the differential effect of acute and chronic caffeine treatment on sleep ontogeny as well as on circadian and homeostatic regulation of sleep in Drosophila. The results of our study showed that acute caffeine treatment reduces day and night sleep in mature flies through the homeostatic pathway whereas it reduced only the day sleep in young flies. Chronic caffeine treatment did not exert any significant effect on sleep in young flies. On the other hand, it delayed the timing of sleep in mature flies and in addition flies under higher caffeine concentration reduced the morning and evening anticipatory activity under 12 hour: 12 hour light: dark cycles. These flies also exhibited either a longer free running period or arrhythmicity under constant darkness. The results of our study showed that acute caffeine treatment suppresses sleep through the homeostatic pathway whereas prolonged caffeine treatment disrupts the circadian rhythm in mature flies.