Académique Documents
Professionnel Documents
Culture Documents
Aim
Understanding Cells tendency of taking irreversible decisions. (Cell signaling pathways are reversible and graded) Applying knowledge to manipulate cellular behavior. (To provide alternate pathways for therapeutic or functional purposes) Designing algorithms of functioning of individual cells and multicellular system. (Unraveling the mechanism of functioning of Brain, Differentiation of Cells or Apoptosis etc)
Electronic Circuits
Transistors for: ON/OFF switches (Bistability) Amplification of Signals Regulation of Current flow. Hysteresis Two or more Inputs with unique Output for a component.
Bistable signal transduction circuits. (a) A double-negative feedback loop. In this circuit, protein A (blue) inhibits or represses B (red), and protein B inhibits or represses A. Thus there could be a stable steady state with A on and B off, or one with B on and A off, but there cannot be a stable steady with both and B on or both A and B off. Such a circuit could toggle between an A-on state and a B-on state in response to trigger stimuli that impinge upon the feedback circuit. (b) A positive feedback loop. In this circuit, A activates B and B activates A. As a result, there could be a stable steady state with both A and B off, or one with both A and B on, but not one with A on and B off or vice versa. Both types of circuits could exhibit persistent, self-perpetuating responses long after the triggering stimulus is removed.
Hysteresis and irreversibility in bistable signaling circuits. (a) Hysteresis. Any bistable circuit should exhibit some degree of hysteresis, meaning that different stimulus/response curves are obtained depending upon whether the system began in its off or its on state. (b) Irreversibility. If the feedback in a bistable circuit is sufficiently strong, the circuit may exhibit true irreversibility, so that the system stays in its on state indefinitely after the triggering stimulus is removed.
AMPK : No Hysteresis Monostable Requires continuous stimulation Positive feedback loop not involved.
Interpretation of Results
Two possibilities: AMPK & JNK not involved in cytochrome c release and another factor responsible for Cell death.
Interpretation of Results
Two possibilities: AMPK & JNK not involved in cytochrome c release and another factor responsible for Cell death. (From literature) AMPK or JNK digital responses alone are not sufficient to induce Apoptosis. Hence require combination of digital responses from different stress sensors (other kinases).
Life as a chip: A digital model for cell decisions. Different stimuli (inputs) are sensed by ultrasensitive protein kinases producing a plethora of analog signals, and some of them are converted into digital signals. The digital responses obtained by the network of kinases are integrated and defines a cellular program, which is translated into a cell decision (outputs). Thus, the generation of digital responses by protein kinases might be the basis for important biological processes: from development to memory.
Analog Responses
All the signals are not completely digital. Graded response also possible. Combination of Digital and Analog responses. Knowledge of all possible pathways and properties of nodes (Protein Kinases), can give well defined algorithm. Can this be extended to an Organ: Brain?
Analog Responses
All the signals are not completely digital. Graded response also possible. Combination of Digital and Analog responses. Knowledge of all possible pathways and properties of nodes (Protein Kinases), can give well defined algorithm. Can this be extended to an Organ: Brain?
Brain
Majority of Protein Kinases expressed in Brain. These Protein Kinases showing Digital Responses. (Hypothesis by author) Physiological concentrations of different stimuli giving digital responses (in Neurons) for different Kinases.
Brain
Memory: Long Term Potentiation (LTP). Mouse learns to reach the Platform in lesser time (experience). LTP is activity dependent strengthening of Does so with aid of visual cue around theSynapses. perimeter. Mice with Hippocampus damaged cant learn. Individual synapses have all-or-none potentiation They can solve if they were trained before brain damage. with different Thresholds (i.e. Digital). Implies that Neurons in Hippocampus necessary for learning. These newly formed neurons are particularly sensitive to LTP. LTP regulated by Kinases (cAMP-dependent Slices from Hippocampus region removed and their CA1 neurons studied in-vitro with(PKA), recording electrodes. protein kinase PKC, MAPK, CaMKII and Repeated stimulation of presynaptic region of these neurons atypical PKC isozyme showed increased sensitivity protein (Plasticity).kinase Mzeta This (PKM plasticity )) is what we refer as LTP (i.e. long-term strengthening
of the synapses between two neurons).
Brain
Memory: Long Term Potentiation (LTP). LTP is activity dependent strengthening of Synapses. Individual synapses have all-or-none potentiation with different Thresholds. Synaptic memories at Hippocampus are encoded in digital manner. LTP regulated by Kinases (cAMP-dependent protein kinase (PKA), PKC, MAPK, Ca2+/calmodulin-dependent protein kinase (CaMKII) and atypical PKC isozyme protein kinase Mzeta (PKM))
Brain
Model for Long Term Memory CaMKII (Digital Kinase) is necessary for LTP in hippocampus. Can be activated different degrees and hence also able to function as frequency detector. CaMKII acts as Bistable switch in postsynaptic density. Which turns on when a threshold number of kinase sites are phosphorylated. Shows Hysteresis for some time due to slow action of Phosphatase. PKM , acts as constitutive kinase, necessary for LTP maintenance and several long term memories.
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