Important words and concepts from Chapter 11, Campbell & Reece, 2002 (1/29/2005):
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(a) Interactions between organisms can range from cooperative to antagonistic. This is true for single-celled organisms and even the individual cells that make up multicellular organisms. As a general rule, cooperation among individuals (or cells) is more likely (though by no means guaranteed) the more genetically similar the cells or individuals are, with nearly complete cooperation occurring particularly when organisms (or cells) are genetically identical plus dependent upon one another for their replication (thereby one cell making babies in a genetic sense is making babies for every genetically identical cell).
(b) Such is the case among the cells that make up most multicellular organisms, and cell-to-cell communication represents how such cells coordinate their physiological behaviors so as to create a cooperative whole, one that is greater than the sum of their cellular parts. This chapter combines bits of endocrinology (the study of hormones), cell biology, and biochemistry to introduce the complexities of the cooperative molecular interactions between cells. When cell-to-cell communication is unsuccessful, a result can be a harmful absence of cooperation, a.k.a., defection, which between cells within a multicellular organism we might recognize as tumors or cancer, as adult-onset diabetes, as developmental abnormalities, etc.
CHEMICAL SIGNALING (BETWEEN CELLS)
(a) Most cell-to-cell communication involves some kind of chemical signaling, including
(i) Chemicals that are allowed to freely diffuse between cells,
(ii) Chemicals that are received by a cell only given cell-to-cell contact, and
(iii) Chemicals that freely diffuse from one cell's cytoplasm to another's via junctions directly linking the cytoplasms of adjacent cells.
(b) See Figure, Local and distant cell communication in animals
(c) See Figure, Communication by direct contact between cells
(e) Alternatively, signals can be byproducts of cellular metabolism that one cell releases essentially as waste or without intending (in an evolutionary algorithm sense) to initiate a signal to another cell, but nevertheless other cells are capable of interpreting those signals and acting on them (e.g., the release of lactic acid from an anaerobically exercising muscle cell)
(f) This chapter considers particularly signaling that involves chemicals that are purposefully released from one cell and allowed to freely diffuse to a second (or more) recipient cell(s) in an act of communication that is deliberately initiated, received, and interpreted in order to increase the physiological coordination of the cells of a multicellular organism
(g) In addition, this chapter's emphasis is particularly on those events that occur following reception of a chemical signal rather than on the purpose of the signal or why and how a given cell released the signal
(a) A local regulator is a chemical signal that influences only neighboring cells
(b) Within an animal this would imply a lack of systemic diffusion which, in turn, suggests that the local regular is not released into the blood or the lymph (which are the routes to systemic diffusion) but instead into the intercellular space/extracellular matrix
(c) Among the localities in which local regulators are active is within the small gaps (called synapses) that occur between nerve cells and between nerve and muscle cells
(a) Unlike local regulators, hormones are chemical signals that diffuse systemically (e.g., diffusion through and are carried by blood and lymph as well as the intercellular space/extracellular matrix)
SIGNAL TRANSDUCTION (INTO CELLS)
(b) We can biochemically differentiate the reception, etc. of these chemical signals into three stages:
(i) Reception (by a cell)
(ii) Transduction (from outside of the cell to inside the cell, etc.)
(iii) Response (how the cell responds to having received the signal)
(c) See Figure, Overview of cell signaling
(d) Most of this chapter is devoted to discussing the complexity of these processes, with particular emphasis on transduction
(a) Reception of a chemical signal literally involves the attachment (or association) of the chemical signal to some aspect of the recipient cell's plasma membrane
(b) The means of reception, typically involving a membrane protein, may be intimately linked to the existence of an intact plasma membrane
(c) A membrane is thus a requirement for the occurrence of subsequent signal transduction and response (i.e., cell-to-cell signaling typically requires that recipient cells are intact)
(c) Transduction is the conversion of the reception signal, typically found at the surface of the cell, to a signal that directly facilitates a response
(d) Very often signal transduction involves a number of steps that, taken as a whole, can be somewhat complex (perhaps overwhelmingly so)
(e) Though not explaining the complexity, nevertheless a basic purpose of the need for signal transduction -- linking reception and response -- is that the plasma membrane receptor and the molecules involved in formulating a response are not always (rarely?) located in the same region of the cell; thus intracellular signals (often chemical) serve to physically connect reception and response
(f) For example, a signal-transduction pathway may involve the following:
(a) The response to cell signaling varies enormously, depending on the signal as well as the receiving cell
(b) Suffice it to say that responses typically involve either the turning on of a specific (often enzymatic) activity (including the synthesis of new enzymes) or a reduction in (or turning off of) a specific enzymatic activity
(c) In addition, a response can involve the turning on or off of more than one activity
(d) "Explanation for the specificity exhibited in cellular responses to signals is the same as the basic explanation for virtually all differences between cells: Different kinds of cells have different collections of proteins. The response of a particular cell to a signal depends on its particular collection of signal receptor proteins, relay proteins, and proteins needed to carry out the response." (p. 202, Campbell et al., 1999)
(e) For the sake of discussion throughout this chapter, consider response to be simply some end point of a signal-transduction pathway
EXAMPLES OF SIGNAL-RECEPTOR PROTEINS
(a) "Most signal molecules are water-soluble and too large to pass freely through the plasma membrane… A cell targeted by a particular chemical signal has molecules of a receptor protein that recognizes the signal molecule. The signal molecule is complementary in shape to a specific site on the receptor and attaches there, like a key in a lock--or like a substrate in a catalytic site of an enzyme. The signal molecule behaves as a ligand, the term for a small molecule that specifically binds to a larger one. Ligand binding generally causes a receptor protein to undergo a change in conformation--that is, to change shape. For many receptors, this shape change directly activates the receptor so that it can interact with another cellular molecule. For other kinds of receptors… the immediate effect of ligand binding is more limited, mainly causing the aggregation of two or more receptor molecules." (p. 192, Campbell et al., 1999)
(b) Membrane-protein signal receptors come in a variety of types including:
(iii) Ion-channel receptors
(c) Some chemical signal molecules, such as steroid hormones, are able to pass through the plasma membrane without the aid of a membrane-protein receptor, allowing reception and transduction to be carried out by the same (intracellular) protein
(a) G-protein-mediated pathways involve at least three components:
(ii) A G protein (responsible for signal transduction)
(iii) And the protein the G protein activates (responsible either for signal transduction or directly effecting the response)
(b) G proteins are signal-transduction proteins that are in an active state when they are bound to a molecule of GTP (similar to ATP except possessing the guanine purine rather than the adenine purine; see Kreb's cycle for another example of the use of GTP in a metabolic pathway)
(d) The G protein interacts with the receptor on the receptor's cytoplasmic side, and conformational changes in the receptor (induced by ligand attachment) results in the activation of the G protein
(e) The G protein diffuses to and then activates a subsequent protein in the signal-transduction pathway (or the protein that is directly responsible for the response) by binding to that protein while in its own (the G protein's) active state
(f) Subsequently, the G protein hydrolyzes the GTP (to GDP) which inactivates the G protein and whatever the active G protein had activated (these activation-after-activation-after-activation pathways can get complicated)
(g) The important function of G protein inactivation is that they allow a reversibility to the G protein mediated activation of a protein, thus contributing to the dynamic nature of a cell
(h) See Figure, The functioning of a G-protein-linked receptor
(a) Tyrosine kinase receptors differ from G protein-linked receptors in three crucial ways
(i) Rather than activating G proteins following their conformational change (that follows ligand binding), tyrosine kinase receptors instead activate their own enzymatic activity, the tyrosine kinase activity and then phosphorylate themselves--the phosphorylated receptor is then recognized by cytoplasmic proteins which effect the transduction event through the cytoplasm
(ii) Part of the process of activation of tyrosine kinase activity involves a dimerization (linking together of two subunits) of the tyrosine kinase receptor
(iii) Individual tyrosine kinase receptors are often capable of directly activating multiple transduction pathways
(b) See Figure, The structure and function of a tyrosine kinase receptor
(c) [tyrosine kinase receptors (Google Search)] [protein kinases in disease (lots of info but heavy going) (The Protein Kinase Resource)] [receptor tyrosine kinase search (The Dictionary of Cell and Molecular Biology)] [index]
(a) A kinase is an enzyme that phosphorylates another protein (or, in the case of a tyrosine kinase receptor, also themselves)
(b) ATP supplies the phosphate group
(c) A tyrosine kinase is thus an enzyme that phosphorylates tyrosine amino acids found on target proteins
(d) [protein kinases (Google Search)] [phosphoprotein database (a collection of proteins that are phosphorylated) (Peter V. Hornbeck)] [protein kinases in disease (lots of info but heavy going) (The Protein Kinase Resource)] [protein kinase search (The Dictionary of Cell and Molecular Biology)] [index]
(b) The important function of protein phosphatases is that they allow a reversibility to the protein-kinase-mediated phosphorylation of a protein, thus contributing to the dynamic nature of a cell
(a) With ion-channel receptors, the molecules responsible for transduction are ions (e.g., Na+ or Ca2+) that are normally found outside of cells
(b) Here binding of a ligand to the receptor (no, the external ions themselves are not the ligands) results in an opening of a gate through the plasma membrane that allows entrance of the ions (both gate and receptor are proteins, likely one in the same protein)
(i) Ligand binding (reception) -->
(ii) Channel opening --> Ion inflow (transduction) -->
(iii) Further transduction or response
(e) See Figure, A ligand-gated ion-channel receptor
AMPLIFICATION OF SIGNALS (WITHIN CELLS)
(a) During signal transduction, signals may be amplified
(c) Recall that enzymes may catalyze a chemical reaction without being used up in the process; thus, one activated protein kinase may phosphorylate many more than one individual target protein
(d) Such activation allows an exponential increase in the number of activated proteins (e.g., one protein activates two, which together activate four, which together activated eight, etc.) which means that the reception of few ligands at the cell surface can lead to dramatic changes in enzyme activity within the cell
(e) "Keep in mind that the original signal molecule is not physically passed along a signaling pathway; in most cases, it never even enters the cell. When we say that the signal is relayed along a pathway, we mean that certain information is passed on. At each step the signal is transduced into a different form, commonly a conformational change in a protein. Very often, the conformational change is brought about by phosphorylation." (p. 195, Campbell et al., 1999)
(f) See Figure, A phosphorylation cascade
(g) See Figure, Cytoplasmic response to a signal: The stimulation of glycogen breakdown by epinephrine
(h) See Figure, Nuclear response to a signal: The activation of a specific gene by a growth factor
(b) "The extracellular signal molecule that binds to the membrane receptor is a pathway's 'first messenger'." (p. 197, Campbell et al., 1999)
(a) Cyclic AMP is an important second messenger
(b) Cyclic AMP is formed from and resembles (though is different from) adensosine monophosphate (cAMP contains a ring that is the result of a dehydration synthesis reaction)
(c) See Figure, Cyclic AMP
(e) See Figure, cAMP as a second messenger
(f) See Figure, Cytoplasmic response to a signal: The stimulation of glycogen breakdown by epinephrine
(c) Cyclic AMP
(d) G protein
(i) Local regulator
(j) Protein kinase
(n) Second messenger
(p) Signal receptor
(a) A signal-transduction pathway that is induced extracellularly in the process of cell-to-cell communication is typically initiated by what? (general term)
(b) Which of the following requires a post-signal-reception dimerization step?
(i) Cyclic AMP
(ii) G protein activation
(iii) Protein phosphatase activity
(iv) Ion-channel formation
(v) Tyrosine kinase-receptor activation
(c) What does the G of G protein stand for?
(d) Give an example of a second messenger.
(e) There are at least three ways that cells may communicate. One involves the diffusion of substances between cells over either short distances or over long distances (paracrine or synaptic signaling and hormones, respectively). A second involves the direct contact between the proteins found on the surfaces of two cells such that the occurrence of that contact signals one or both participating cells via a transduction of that contact information through the plasma membrane(s) into the adjacent cytoplasm(s). What is the third means by which cells may communicate?
(f) Distinguish "second messenger" from " primary or first messenger" in signal transduction. That is, how do these two molecule types differ other than that one is temporally involved prior to the other.
(g) Given that a signal has been released by one (sending) cell, what then are the three subsequent (general) steps of cell signaling?
(h) What is the first thing that tyrosine kinase receptors enzymatically (i.e., catalytically) do following signal reception?
(i) What steps are typically involved in G protein-linked receptor signal transduction? Consider only those steps that directly involve the G protein. By my count, following ligand binding and the resulting receptor conformational change, there are approximately 8 steps including the various binding and diffusion steps.
(j) What is the first step of signal transduction, i.e., that is directly and immediately induced by ligand binding at the surface of a cell?
(k) For ion-channel receptors, what is the general name of the substance that binds to the receptor thereby initiating the signal transduction process?
(l) A chemical cell-to-cell signal that influences only neighboring cells is said to be a(n) __________ regulator.
(m) In the three general steps of cell signaling, transduction represents which step: One, Two, or Three? (assume temporal order)
(n) Name a cell-to-cell signal (or specific category of signals) whose reception does not involve a membrane protein.
(o) If signal reception occurs at the plasma membrane and response occurs, for example, in or at the nucleus, then where in the cell does signal transduction occur? Assume no second messengers.
(p) What is a ligand?
(q) Which do you not observe in or is not a property of a protein kinase receptor?
(ii) Ion channel
(iii) Ligand binding
(iv) Membrane protein
(r) What reaction does a protein phosphatase typically catalyze? Be sure to indicate both substrate(s) and product(s)
(s) What is the name of the second messenger that structurally resembles adenosine monophophate?
(t) Within multicelled orgnanisms cell-to-cell communication typically promotes __________ interactions between genetically identical cells.
(u) Chemical signaling between cells can involve direct cell surface-to-surface contact, diffusion of chemicals through the fluid between cells (either through the extracellular matrix or more systemically through blood or lymph), and diffusion of chemicals from one cell to another via __________.
(ii) Gap junctions
(iii) Intermediate filaments
(iv) Tight junctions
(v) Proton pumps
(v) Whereas a local regulator is a chemical that diffuses within intercellular spaces, a hormone is a signaling chemical that diffuses __________.
(w) What relatively small molecule is associated with activated but not inactive G proteins?
(x) What enzymes are associated with the inactivation of proteins activated by a protein kinase?
(y) Signal amplification in cell-to-cell communication often involves protein kinases. Explain how one ligand, via signal amplification involving more than two protein kinases, can quickly give rise to, for example, a million signal molecules within a cell's cytoplasm.
(z) Give an example of a second messenger, one that is an organic compound.
(aa) What are the three general stages of a signal-transduction pathway (a.k.a., less precisely, the beginning, middle, and end)?
(bb) Explanation for the specificity exhibited in cellular responses to signals is the same as the basic explanation for virtually all differences between cells. What is the explanation?
(cc) What is a ligand?
(i) A membrane protein
(ii) A plasma membrane
(iii) A signal transduction pathway
(iv) A small molecule
(v) An ion channel receptor
(dd) G proteins are signal-transduction proteins that are in an active state when they are bound to a molecule of __________.
(ee) Part of the process of activation of tyrosine kinase activity involves __________ of the tyrosine kinase receptor.
(i) Dephosphorylation of themselves
(iii) Hydrolysis of G protein
(iv) Synthesis of ATP
(ff) What is the reaction catalyzed by a protein phosphatase?
(gg) Cyclic AMP _________.
(i) Can serve as a ready source of energy in cells
(ii) Can serve as a second messenger
(iii) Is hydrolyzed by G proteins
(iv) Is hydrolyzed by protein kinases
(v) Is involved in signal reception
(a) The binding of a ligand to a cell-surface receptor
(b) (v) Tyrosine kinase-receptor activity
(c) Guanosine as in GTP
(e) The (a) third way that cells may is via the free diffusion of chemicals from one cell's cytoplasm to another via junctions that directly link the cytoplasms of adjacent cells
(f) Secondary messengers are small, water soluble, non-proteinaceous… capable of rapid diffusion through the cytoplasm
(g) Reception, transduction, response
(h) Tyrosine kinase receptors phosphorylate the tyrosine residues on adjacent subunits following ligand binding; note that an intervening step involves receptor dimerization, but this presumably is not an enzymatic process
(i) G protein-linked receptor signal transduction involves (starting following ligand binding): (i) binding of G protein to receptor, (ii) loss of GDP from G protein, (iii) gain of GTP by G protein (thereby activating it), (iv) diffusion along membrane toward subsequent protein in signal transduction pathway, (v) binding to subsequent protein, (vi) activation of subsequent protein, (vii) hydrolysis of GTP to GDP, and (viii) diffusion of G protein away from subsequent protein.
(j) Conformational change of the receptor protein is typically the first step of signal transduction following ligand binding
(k) Ligand binding initiates signal transduction with ion-channel receptors, not ions (the channel opening that lets ions into the cell is how the signal is transduced into the cell)
(n) Steroids; e.g., testosterone
(p) A ligand is a small molecule that binds to a larger molecule as in the binding of a signal molecule to the larger receptor molecule
(q) (ii) Ion channel
(r) Protein phosphatases typically catalyze the removal of a phosphate from a protein
(s) Cyclic AMP (cAMP)
(t) (iii) Cooperative
(u) Direct diffusion from one cytoplasm to another
(v) Systemically; through the blood, or through the lymph
(x) Protein phosphatases
(y) The activation of a single protein kinase (call it A) can lead to the activation (by phosphorylation) of, say, 100 downstream protein kinases (of type "B"), each of which could activate 100 protein kinases of type "C", each of which could activate another protein kinases of type "D"; 100 x 100 x 100 = 1,000,000
(aa) Reception, Transduction, Response
(bb) Different kinds of cells have different collections of proteins
(cc) (iv) A small molecule
(ee) (ii) Dimerization
(ff) Removal of a phosphate group from a protein
(gg) (ii) Can serve as a second messenger
(bonus 2) Fill in the two blanks:
Chapter 11, Bio 113 questions:
(#) Contrast Local Regulator and Hormone.
A: Hormones act systemically, entering the blood or lymph; by contrast, local regulators do not enter the blood or lymph and therefore can affect only those cells that are physically quite close
(#) What are the three general steps of cell-to-cell signaling as experienced by the receiving cell?
A: Reception, Transduction, and Response
(#) Explanation for the specificity exhibited in cellular responses to signals is the same as the basic explanation for virtually all differences between cells: Different kinds of cells have different collections of __________.
(#) What is a ligand?
A: A ligand is a small molecule (such as a hormone) that specifically binds to a larger molecule (such as a receptor protein)
(#) True or False, the G protein interacts with G protein-linked receptors on the cytoplasmic side of the plasma membrane.
(#) Tyrosine kinase receptors differ from G protein-linked receptors in three crucial ways. Name two.
A: The tyrosine kinase receptors activate themselves rather than another protein and then interact with subsequent proteins in the signal-transduction pathway by themselves rather than through the equivalent of an activated G protein intermediary; the tyrosine kinase receptors form dimers upon activation; the tyrosine kinase receptors are capable of directly activating multiple transduction pathways
(#) What is the catalytic activity of a protein phosphatase?
A: protein phosphatases dephosphorylate other proteins
(#) "Keep in mind that the original signal molecule is not physically passed along a signaling pathway; in most cases, it never even enters the cell. When we say that the signal is relayed along a pathway, we mean that certain information is passed on. At each step the signal is transduced into a different form, commonly a __________ change in a protein. Very often, the __________ change is brought about by phosphorylation." Note that the same word is used for both blanks.
(#) What is a second messenger?
A: A second messenger is a non-protein molecule that participates in signal transduction
(#) Name a common kind of second messenger derived from ATP.
A: cAMP = cyclic AMP