Cellular Participation In Physiology. Jim Pierce Bi 145a Lecture 3, 2009-2010. Cellular Physiology. There is more to cells than just performing basal functions. Cellular Physiology is the study of how cells perform both basal and tissue specific functions.
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Cellular ParticipationIn Physiology Jim Pierce Bi 145a Lecture 3, 2009-2010
Cellular Physiology There is more to cells than just performing basal functions. Cellular Physiology is the study of how cells perform both basal and tissue specific functions. It is the bridge between molecular biology and tissue function.
Cellular Physiology General Cellular Physiology The study of inputs, metabolism, and outputs. Our goal for this lecture is to look at examples of inputs and outputs.
Cellular Physiology Specific Cellular Physiology This is the study of specific aspects of cellular function. Our goal in this lecture is to discuss some of the common functions: membrane function, cellular structure, cellular motors, and secretion.
General Cell Physiology Homeostasis versus Active Function Often, we want to do more than“cruise along” at status quo. This means doing stuff
Homeostasis What is homeostasis? It is central to understanding physiology, and makes metabolism much easier. It is the property of a system to try to maintain constancy in the face of external perturbations.
Homeostasis Regulation When a system maintains some variable despite internal or external perturbation. Control When a force adjusts the output of a system over time. Refrigerator Thermostat Glycogen in a Myocyte
Homeostasis Figuring out the Refrigerator is easy The thermostat controls The “dial” indicates the set point A circuit in the Refrigerator regulates. It compares the actual temperature to the thermostat’s set point It heats or cools accordingly
Homeostasis Glycogen is not so easy. What controls glycogen levels? There is no thermostat. The myocyte does not receive a specific “glycogen level signal.”
Homeostasis What controls glycogen levels? There are external signals that inform the myocyte of the state of the body. There are internal signals that inform the myocyte of the state of the cell. The cell must integrate these signals to make that decision.
Homeostasis The way a cell integrates these signals to make that decision is calledA Control Structure
Homeostasis How is glycogen level regulated? Because there is no thermostat,it is not a simple “compare” like the fridge Instead the pathway “pays attention” to every reaction, intermediate, and final product This is called a Regulatory Structure
Homeostasis How is glycogen level regulated? The Regulatory Structure is affected by the Control Structure. It is through those interactions thatthe Regulatory Structure obeys theControl Structure
Homeostasis What makes up these structures? Cells Do Chemistry. (they do physics, too, but I don’t like physics so I won’t talk about it) Chemical Compounds (stuff) Processes Involving Chemical Compounds (a way to change stuff)
Homeostasis Structures are composed of reactions A B C D E F
Metabolism supply demand Xsource --> M --> Xsink (in a nutshell)
Regulatory Network supply demand Xsource --> M --> Xsink (in a nutshell)
Control Network supply demand Xsource --> M --> Xsink (in a nutshell)
Why is this confusing? The final product has the greatest effect on the flux through metabolism So the USE of the final product exerts CONTROL
Regulation versus Control So certain Regulatory structures give“Control” to the end product This is probably why biologists use “regulate” and “control” interchangeably Just remember, like precision and accuracy, control and regulation are different!
Metabolism and its Control So how do we describe these things? We start with a Model of the system
Metabolic Pathway A B C D A set of metabolites and reactions involving those metabolites. (note that a metabolic pathway can be described by graph theory)
Generalized Linear Metabolic Pathway A B C D
Control and Regulation We can then describe how any given thing (enzyme, molecule, extrinsic parameter) affects any other given thing This gives a bunch of variables This allows a mathematical model
Control in Dynamical Systems Models That Exist: Linear Systems Linear Models Non-Linear Systems Non-Linear Models Linear Models If you want to learn more Take CDS 101, 110
Metabolism There is more to metabolism than just the graph of the reactions Location of the reactions Cytosolic, Membrane Bound, Nuclear Job in “the bigger picture” Anabolism versus Catabolism
Control by Supply Feedforward Control: 1) Can achieve high control of flux 2) High control of flux forces us to have low control of metabolites! (That means AMPLIFICATION)
Control By Demand Feedback Control 1) Can achieve high control of flux 2) High control of flux forces us to have high control of metabolites!
Metabolic Control Analysis We can prove that: 1) Feedback is the way we get control of both flux and concentration. 2) Feedforward is the way we get control of flux and amplification.
Internal State The first consideration in “doing stuff”is the Internal State of the Cell The set of DNA, RNA, and protein (especially “transcription factors”) Organelles and Compartmentalization Membrane and its Potential Secondary messengers
Internal State Sometimes, the decision to Activateis the Internal State The best studied example is Cell Cycle There is an internal clock(multiple, actually) In many cases, the ticking of the clock alone is the largest stimulus for cell division
Internal State A closely related (and more interesting) example is Early Development Much of the earliest patterning results from internal state Distribution of Bicoid mRNA (Drosophila) Distribution of Vg-1 protein (Xenopus) Random Genetic and Positional Noise(Chick rotates with gravity, Mouse random based on position in ICM) (Bi 182 for more info!)
Internal State Other basal functions include: Basal secretion in glands Basal membrane potential patterns Anabolism and Catabolism for Housekeeping
Internal State In the case of cell cycle,the output includes: Replicating DNA and organelles Nuclear Division Cytosol Division A huge number of checkpoints Lots of error correcting
Internal State In the case of early developmentthe output consists of: Spacial and Temporal Patterningof space (intra and extracellular) Interpreting “Internal state” intoCellular Phenotype
General Cell Physiology Obviously, though, internal state cannot be the only cue! In a complex organism, even making ATP depends on the state of the organism! (a fat cell should never steal glucose from a starving brain cell)
General Cell Physiology Types of Inputs: Small Molecules Neurotransmitters, Steroids, Peptides Non steroid, non peptide hormones
General Cell Physiology Types of Inputs: Large Molecules ICAMs, Selectins, Integrins Lipoproteins Other Immunoglobulins Other Glycoproteins
Small Molecules Why Small Molecules? They are very versatile They can carry information (in both concentration and concentration gradient) They can diffuse or be transported.
Small Molecules Why Small Molecules? They are very efficient The earliest “computation” on small molecules was probably bacterial chemotaxis Food (i.e. reduced molecules) was transduced into swimming behavior
Small Molecules Why Small Molecules? They are very efficient This system can be harnessed by using specific small molecules as a signal Ever notice that many neurotransmitters are decarboxylated amino acids?
Small Molecules Examples of Small Molecules Addition / Integration Two inhibitory cells both release GABA onto the same dendrite, increasing hyperpolarization Each parathyroid cell releases hormone into the blood, and response is a function of “total hormone” levels.
Small Molecules Retention Insulin binds to its receptor and is internalized, providing continued signaling. Degredation Serum Catecholamine-O-Methyl-Transferase has different rates of catecholamine removal than neuronal reuptake machinery
Small Molecules Gradient Retinoic Acid (vitamin A) and HOX genes DPP in certain non-mammal animals Target Autocrine – stimulates self Paracrine – stimulates neighbor Neurocrine – neural synapse Endocrine – stimulates distant cell via blood Neuroendocrine – neural secretion into blood
Large Molecules Why Large Molecules? They can “mark” an area of extracellular space. (i.e. they stay put) They convey information about tissue structure (both cell-cell and cell-ECM).
Large Molecules Consider Neural Crest Cells Early development “encodes” space with a set of small molecules, gradients, and large molecules. Neural crest cells migrate through this space, using the cellular computer to respond to spacial differences