Control Systems and Cell Communication

Flashcards covering homeostasis control systems, feedback loops, cellular signal transduction mechanisms, neurotransmitter synthesis and pathways, receptor classifications, catalytic/intracellular signaling, apoptosis, and physiological integrations.

What four actions must a physiologic control system perform to maintain homeostasis?

1. SENSE the regulated variable (vital parameter). 2. COMPARE the input signal with an internal reference value called the set point. 3. MULTIPLY the error signal by a proportionality coefficient (the gain) to produce an output signal. 4. ADJUST the regulated variable by activating effector system(s).

In the PaCO2 negative feedback loop example, what components act as the regulated variable, sensors, feedback controller, and effectors?

The regulated variable is PaCO2; the sensors are central chemoreceptors in the retrotrapezoid nucleus of the medulla; the feedback controller is the dorsal respiratory group (DRG) / central pattern generator (CPG); and the effectors are the muscles of inspiration.

What are three physiological examples of beneficial positive feedback loops cited in the lecture notes?

1. Childbirth (parturition). 2. The blood coagulation cascade. 3. The opening of voltage-gated $Na^+$ channels to initiate and propagate an action potential.

What four categories of input information arrive at cells for signaling?

1. Purely physical energy (light, sound, heat, pressure, electricity). 2. Chemical signals (neurotransmitters, hormones, eicosanoids, drugs, toxins). 3. Cellular signals (gap junctions). 4. Extracellular matrix molecules (collagen, integrins, laminin).

How are weak noncovalent forces ordered from weakest to strongest in terms of receptor specificity?

van der Waals < hydrophobic < hydrogen < ionic < covalent

What are the six sequential processes in signal transduction?

1. Recognition of the signal by its receptor. 2. Transduction of the extracellular message into an intracellular signal. 3. Transmission of the second messenger's signal to effectors. 4. Modulation of downstream chemicals. 5. Response of the cell. 6. Termination of the response.

What are the four primary categories of receptor-based signal transducers?

1. Transmembrane G protein-coupled receptors (GPCR). 2. Transmembrane gated ion channels. 3. Transmembrane enzyme-linked (catalytic) receptors. 4. Soluble nuclear (intracellular) receptors.

Which chemical messengers are derived from arachidonic acid?

Eicosanoids (prostaglandins, leukotrienes, thromboxanes, HETEs, and EETs) and endocannabinoids (anandamide and 2-arachidonylglycerol).

What structural characteristic defines all heterotrimeric G protein-coupled receptors?

A plasma membrane receptor with seven transmembrane helical segments (7-TM, seven-helix, or serpentine receptor).

How does ligand binding to a GPCR activate the heterotrimeric G protein complex?

Ligand binding induces a conformational change in the GPCR that facilitates the release of bound GDP and simultaneous binding of GTP to the \text{G}\text{\textalpha} subunit, causing dissociation of the heterotrimeric \text{\textalpha}\text{\textbeta}\text{\textgamma} complex into a free GTP-bound \text{\textalpha} subunit and a separate \text{\textbeta}\text{\textgamma} complex.

What are the four heterotrimeric G protein families and their primary intracellular targets?

1. $G_s$: Stimulates adenylyl cyclase. 2. $G_{i,O}$: Inhibits adenylyl cyclase. 3. $G_{q,11}$: Stimulates phospholipase C (PLC). 4. $G_{12,13}$: Activates small G proteins.

How do Cholera toxin and Pertussis toxin pathologically alter G protein function?

Cholera toxin chemically alters the $G_s$ subunit to inhibit its intrinsic GTPase activity, leading to continuous activation of adenylyl cyclase and excess $cAMP$. Pertussis toxin chemically alters $G_{i,O}$ subunits to interrupt their interaction with receptors, suppressing $G_{i,O}$ effects and overactivating adenylyl cyclase.

What second messengers are generated by Adenylyl Cyclase, Phospholipase C, and Phospholipase A2?

1. Adenylyl cyclase (AC) converts ATP to cyclic adenosine monophosphate ($cAMP$). 2. Phospholipase C (PLC) converts $PIP_2$ to inositol triphosphate ($IP_3$) and diacylglycerol ($DAG$). 3. Phospholipase A2 (PLA2) liberates arachidonic acid to produce eicosanoids.

How does Diacylglycerol ($DAG$) function as a second messenger?

$DAG$ remains anchored in the plasma membrane where it acts as a docking site for and activator of Protein Kinase C (PKC) in conjunction with $Ca^{+2}$.

How does Inositol trisphosphate ($IP_3$) trigger intracellular calcium release?

Soluble $IP_3$ diffuses through the cytoplasm and binds to ligand-activated $Ca^{+2}$ channels on the endoplasmic reticulum (ER), releasing stored $Ca^{+2}$ into the cytoplasm.

What role does Calmodulin play in $Ca^{+2}$ signal transduction?

Calmodulin (CaM) is a $Ca^{+2}$-sensing protein; when 3 to 4 $Ca^{+2}$ ions bind to CaM, it undergoes a conformational change to form an active $Ca^{+2}/\text{CaM}$ complex that modulates downstream targets such as nitric oxide synthase (NOS), adenylyl cyclase, and myosin light-chain kinase.

What structural features distinguish chemical synapses from electrical synapses?

Electrical synapses connect cells directly via gap junctions composed of two connexon hemichannels for bi-directional flow. Chemical synapses are polarized for one-way communication and consist of a presynaptic terminal, a $20\text{--}40\text{ nm}$ synaptic cleft, and a postsynaptic membrane density.

What is the difference between ionotropic and metabotropic neurotransmitter receptors?

Ionotropic receptors are ligand-gated ion channels that open directly upon ligand binding to produce fast synaptic responses (milliseconds). Metabotropic receptors are G protein-coupled receptors (GPCRs) that activate secondary enzymatic cascades to produce slower responses (seconds to minutes).

What presynaptic mechanism triggers neurotransmitter exocytosis at chemical synapses?

Action potential depolarization opens presynaptic voltage-gated N-type $Ca^{+2}$ channels; the resulting influx of $Ca^{+2}$ is detected by synaptotagmin in the docking protein complex, triggering synaptic vesicle fusion with the presynaptic membrane.

What are the rate-limiting steps in the synthesis of Acetylcholine, Catecholamines, and Serotonin?

• Acetylcholine: The active transport of choline into the presynaptic terminal. • Catecholamines: The conversion of tyrosine to L-DOPA by tyrosine hydroxylase. • Serotonin: The hydroxylation of L-tryptophan by tryptophan hydroxylase.

What is the subunit composition and activation requirement of adult skeletal muscle nicotinic acetylcholine receptors ($N_M$)?

$N_M$ receptors are pentameric complexes with subunit composition (\text{\textalpha}_1)_2\text{\textbeta}_1\text{\textdelta}\text{\textepsilon}. Opening requires the simultaneous binding of two acetylcholine molecules to the two \text{\textalpha} subunits at the \text{\textalpha}/\text{\textepsilon} and \text{\textalpha}/\text{\textdelta} interfaces.

Which G protein alpha subunits are linked to muscarinic acetylcholine receptor subtypes M1 through M5?

Muscarinic receptors M1, M3, and M5 (odd numbers) are coupled to $G_{q,11}$ (activating PLC). Receptors M2 and M4 (even numbers) are coupled to $G_{i,O}$ (inhibiting adenylyl cyclase and opening GIRK $K^+$ channels).

What enzymatic sequence synthesizes Epinephrine from Tyrosine?

Tyrosine $\rightarrow$ L-DOPA (via tyrosine hydroxylase) $\rightarrow$ Dopamine (via aromatic L-amino acid decarboxylase) $\rightarrow$ Norepinephrine (via dopamine \text{\textbeta}-hydroxylase inside vesicles) $\rightarrow$ Epinephrine (via phenylethanolamine-N-methyltransferase [PNMT] in cytoplasm).

What enzymes degrade Norepinephrine and Epinephrine, and what is the primary urinary metabolite?

Norepinephrine and Epinephrine are degraded by Monoamine Oxidase (MAO) and Catechol-O-methyltransferase (COMT). The primary end-product excreted in urine is Vanillylmandelic acid (VMA).

What are the three required conditions ('safety locks') for full activation of the N-methyl-D-aspartate (NMDA) receptor?

1. Binding of two glutamate molecules. 2. Binding of two glycine co-agonist molecules. 3. A depolarizing membrane voltage change to relieve the $Mg^{+2}$ pore block.

What is excitotoxicity and what cellular mechanism causes it?

Excitotoxicity is neuronal injury or programmed cell death (apoptosis) caused by excessive glutamate receptor activity leading to uncontrolled influx of intracellular $Ca^{+2}$.

Which intravenous anesthetic agents target the ionotropic $GABA_A$ receptor?

Benzodiazepines, barbiturates, propofol, etomidate, and volatile anesthetics all target the $GABA_A$ receptor.

What reaction does Nitric Oxide Synthase (NOS) catalyze to synthesize Nitric Oxide?

NOS catalyzes the conversion of L-arginine, $NADPH$, and $O_2$ into L-citrulline, $H_2O$, and Nitric Oxide (NO).

How does Nitric Oxide (NO) induce relaxation in vascular smooth muscle cells?

NO diffuses into vascular smooth muscle and activates soluble guanylyl cyclase (sGC), which converts GTP to $cGMP$. $cGMP$ activates downstream signaling and $K^+$ channels to cause hyperpolarization and muscle relaxation.

What are the five major categories of enzyme-linked (catalytic) receptors?

1. Receptor guanylyl cyclases. 2. Receptor tyrosine kinases (RTKs). 3. Tyrosine kinase-associated receptors. 4. Receptor serine/threonine kinases. 5. Receptor tyrosine phosphatases.

How do Receptor Tyrosine Kinases (RTKs) initiate signaling upon binding ligands such as insulin?

Ligand binding causes receptor dimerization and triggers auto- and cross-phosphorylation of cytoplasmic tyrosine residues, recruiting scaffold proteins like insulin receptor substrate (IRS) to activate downstream cascades.

How do steroid hormone receptors differ from thyroid hormone receptors in location and dimerization?

Steroid hormone receptors are soluble cytoplasmic or nuclear receptors that form homodimers (e.g., PR-PR). Thyroid hormone receptors (TR) are pre-bound to DNA in the nucleus and form heterodimers with the retinoic acid receptor (TR-RXR).

What features distinguish cell death by apoptosis from necrosis?

Necrosis involves uncontrolled cell swelling, plasma membrane disruption, leakage of contents, and frequent surrounding inflammation. Apoptosis is genetically programmed cell shrinkage with intact plasma membranes, DNA fragmentation, packaging into apoptotic bodies, and no inflammation.

What are the key initiator and executioner caspases involved in apoptosis?

Initiator caspases are CAS-2, -8, -9, and -10. Executioner (effector) caspases are CAS-3 and -7.

What membrane phospholipid alteration acts as an 'eat-me' signal for phagocytes during apoptosis?

Caspases activate enzymes that flip phosphatidylserine (PS) from the inner (cytosolic) membrane leaflet to the outer leaflet of the plasma membrane.

How do presynaptic and postsynaptic opioid receptor signaling pathways produce analgesia?

Presynaptically, G_{\text{\textbeta}\text{\textgamma}} subunits block voltage-gated N-type $Ca^{+2}$ channels to decrease $Ca^{+2}$ influx and reduce neurotransmitter release. Postsynaptically, G_{\text{\textalpha}i} subunits inhibit adenylyl cyclase and open GIRK $K^+$ channels to hyperpolarize the membrane.

How does Vasopressin act at V2 receptors in renal principal cells to promote water reabsorption?

Vasopressin binds basolateral $V_2$ receptors ($G_s$-coupled), activating adenylyl cyclase to raise $cAMP$. $cAMP$ activates PKA, which phosphorylates aquaporin-2 (AQP2) and stimulates exocytosis of AQP2 channels into the apical membrane.

What are the primary target phosphodiesterases (PDE) and clinical applications for Milrinone, Roflumilast, and Sildenafil?

• Milrinone: Selective PDE3 inhibitor (inodilator used for cardiac contractility and vasodilation). • Roflumilast: Selective PDE4 inhibitor (used to treat COPD). • Sildenafil: Selective PDE5 inhibitor (used for erectile dysfunction and pulmonary hypertension).