Calmodulin (CaM) is a key signaling protein that plays a decisive role in mitochondrial Ca2+ homeostasis and signaling and modulates the mitochondrial membrane properties. We propose that voltage-dependent anion channel 1 (VDAC1), one of the most abundant outer mitochondrial membrane (OMM) proteins, could be its possible target or site of action. VDAC1 is known to play a crucial role in the mitochondrial Ca2+ signaling mechanism. Bilayer electrophysiology experiments show that CaM significantly reduces VDAC1’s conductivity and modulates its gating as well as permeability properties. Also, spectrofluorimetric analysis indicates the possibility of binding CaM with VDAC1. Theoretical analysis of fluorescence data shows that the aforementioned protein–protein interaction is not linear, but rather it is a complex nonlinear process. In VDAC1, CaM binding site has been predicted using various bioinformatics tools. It is proposed that CaM could interact with VDAC1’s outer-loop region and regulate its gating properties. Our findings suggest that VDAC1–CaM interaction could play a crucial role in the transport of ions and metabolites through the OMM and the regulation of the mitochondrial Ca2+ signaling mechanism through alteration of VDAC1’s gating and conductive properties.

From the perspective of learning and memory, intrinsic plasticity of neurons is an immensely important phenomenon. The hallmark of intrinsic plasticity is detectable in the form of activity dependent reduction in the After Hyper-polarization. But, as of now, it is not very clearly understood how neurons manage to do this. Keeping this in view, the dynamics of After Hyper-polarization reduction in a single neuron has been investigated in this work. The approach that has been adopted is that of biophysical modeling based on the Hodgkin-Huxley equation of Action Potential. The parameters in the Hodgkin-Huxley equations, which contribute to the threshold and the reduction of After Hyper-polarization, have been investigated in different neuron types, namely, the classical Hodgkin Huxley squid giant neuron, rodent cortical pyramidal neuron and rodent hippocampal interneuron. The potassium reversal potential (V K ) has been found to be the Hodgkin Huxley parameter that modulates the After Hyper-polarization in all kinds of neurons. The potassium reversal potential (V K ) has been modeled as sigmoid and modified exponential function of the number of input stimulus. Computational results show that increase in the number of input stimulus results in decrease in After Hyper-polarization.

Ion channels self-organize on cellular and organelle membranes as clusters and mutually modulate their gating behavior. It has been reported that the efficient information transfer is achieved by cooperative clustering of ion channels. To address the origin and nature of collective dynamics in ion channel clusters, a statistical mechanical model, namely, the Zimm–Bragg-type model in two dimensions with unequal weight distribution in channel–channel interactions, has been proposed. Nearest neighbor interaction along with next-nearest neighbor interaction has been considered, assuming symmetric spatial organization. The multichannel bilayer electrophysiology recordings of the voltage-dependent anion channel (VDAC) from rat brain mitochondria have been analyzed in order to test and further extend the model. The model successfully describes the multichannel gating behavior and self-organization of the VDAC cluster.

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is a key enzyme that plays a significant role in intracellular signaling and the modulation of mitochondrial membrane properties. It is known that the voltage-dependent anion channel (VDAC) is one of the most abundant outer mitochondrial membrane (OMM) proteins acting as a significant passageway and regulatory site for various enzymes, proteins, ions, and metabolites. Considering this, we hypothesize that VDAC could be one of the targets for CaMKII enzymatic activity. Our in vitro experiments indicate that VDAC can be phosphorylated by the CaMKII enzyme. Moreover, the bilayer electrophysiology experimental data indicate that CaMKII significantly reduces VDAC's single-channel conductivity; its open probability remains high at all the applied potentials between +60 and −60 mV, and the voltage dependency was lost, which suggests that CaMKII disrupted the VDAC's single-channel activities. Hence, we can infer that VDAC interacts with CaMKII and thus acts as a vital target for its activity. Furthermore, our findings suggest that CaMKII could play a significant role during the transport of ions and metabolites across the outer mitochondrial membrane (OMM) through VDAC and thus regulate apoptotic events.

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