Cell Signaling and Renal Physiology Concepts

• Neonicotinoids prevent acetylcholine from binding to its receptors in the postsynaptic neuron, thus stopping signal initiation.
• The binding of Neonicotinoids is irreversible because acetylcholinesterase does not degrade them.
• Neonicotinoids are more effective insecticides because they selectively bind to insect acetylcholine receptors with a higher affinity than to mammalian receptors.
• Steroid hormones, such as cortisol, testosterone, and estrogen, are lipid-derived molecules synthesized from cholesterol.
• Protein hormones, such as antidiuretic hormone (ADH) and insulin, consist of amino acid chains.
• Acetylcholinesterase terminates acetylcholine's action at the synapse by breaking it down and if destroyed causes continuous stimulation.
• Termination of muscle contraction is ensured as Acetylcholinesterase breaks down acetylcholine in the synaptic cleft.
• Nitric oxide (NO) modulates synaptic activity via cGMP signaling pathways, disrupting cGMP synthesis would directly affect NO signaling.
• Water-insoluble ligands must cross the plasma membrane to bind and activate intracellular receptors in the cytoplasm or nucleus.
• Adenylate cyclase converts ATP into cyclic AMP (cAMP), and cAMP acts as a second messenger in the epinephrine signaling pathway.
• Water reabsorption is prevented from the collecting ducts, producing more dilute urine due to reduced water permeability often due to ADH inhibition.
• Increased ADH, aldosterone, or RAAS would promote water retention and more concentrated urine.
• Protein kinases amplify signals by adding phosphate groups to other proteins, creating a phosphorylation cascade.
• Glutamate is an excitatory amino acid, and GABA is an inhibitory amino acid.
• High osmotic concentration in the kidney medulla, driving osmosis in the descending limb and collecting ducts, is created by the active transport of sodium ions in the ascending limb.
• Adenylate cyclase is continuously activated and PKA activation is prolonged if the alpha subunit cannot hydrolyze GTP and it remains active.
• Neurotransmitters are released when an action potential reaches the axon terminal which causes calcium channels to open, and the influx of calcium ions.
• Amines (melatonin, epinephrine, and norepinephrine), peptide hormones (Insulin, oxytocin, FSH, and growth hormones), and steroid/lipid hormones (Oestradiol, testosterone, cortisol) are the three subunits of hormones secreted by endocrine cells.
• Neurons communicate with each other in milliseconds as Amino acids - glycine, glutamate and GABA (Gamma-aminobutyric acid) are involved in fast synaptic transmission.
• Neuropeptide Y increases the motivation to eat food and is an example of a peptide neurotransmitter that is responsible for a number of physiological and homeostatic processes.
• Serotonin regulates mood, dopamine is involved both in reward-seeking behavior and in regulation of movement, and norepinephrine (noradrenaline) controls the fight or flight response are examples of amines - Biogenic amines are modified amino acids.
• Nitrous oxide (NO) modulates how neurons communicate with each other by regulating the release of other neurotransmitters, is a gas(laughing gas) that acts as a neurotransmitter and is used as a sedative by dentists.
• G proteins can bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP) and are specialized proteins.
• GTP, like ATP, is involved in energy transfer within the cell.
• G proteins act like molecular switches when bound to G protein-coupled receptors (GPCRs) present in the plasma membrane.
• There are around 800 GPCRs, and each GPCR is specific to a particular function including affecting taste, smell, behaviour and mood, they are also targets of many medicinal drugs whose ligands range from neurotransmitters and hormones to odors and light-sensitive compounds.
• inactive α subunit is bound to GDP G proteins consist of three subunits – α, β and γ.
• When a ligand binds to a GPCR, the alpha subunit separates from the beta and gamma subunits and transitions between an inactive state (bound to GDP) and an active state (bound to GTP).
• The beta/gamma subunit can activate other transduction pathways and the activated alpha subunit can activate downstream effectors of various transduction pathways in the cell.
• Epinephrine (aka adrenaline) prepares the body for a "fight or flight" response.
• Skeletal muscles need to be supplied with lots of glucose for energy when bodies anticipate intense physical activity.
• Epinephrine receptors in the liver are GPCRs and Glycogen, a polysaccharide of glucose, is stored in the liver.
• The activated alpha-GTP complex activates multiple copies of a downstream enzyme (adenylate cyclase) embedded in the membrane when epinephrine binds to this receptor.
• These embedded enzymes convert multiple ATP molecules to cAMP molecules (cyclic adenosine monophosphate) which act as second messengers, activating multiple protein kinase A enzymes which phosphorylate an enzyme in the liver that hydrolyzes stored glycogen into glucose.
• Glucose moves from the filtrate in the nephron into the bloodstream during normal kidney function through active transport and this occurs in the proximal convoluted tubule.
• Movement of water into blood is influenced by the hormone ADH.
• Reabsorption of water in the collecting duct in the kidney is stimulated by ADH.
• Neurons with free nerve endings in the skin, known as nociceptors, detect and transmit pain signals in response to potentially harmful stimuli.
• Nociceptors generate action potentials that travel along their axons to the spinal cord, where they synapse with secondary neurons in the dorsal horn and have receptors that respond to mechanical, thermal, or chemical stimuli that may indicate tissue damage.
• Signal transmission to higher brain centers, including the thalamus and somatosensory cortex, where pain is processed and perceived, is facilitated by neurotransmitters such as glutamate and substance P.
• Excitatory neurotransmitters, such as glutamate, depolarize the postsynaptic membrane by opening ion channels that allow positive ions (e.g., Na*) to enter, while inhibitory neurotransmitters, like GABA and glycine, hyperpolarize the postsynaptic membrane by opening channels for negative ions (e.g., Cl¯) or causing K⁺ efflux.
• The postsynaptic neuron integrates multiple excitatory and inhibitory signals in the process of summation and if excitatory inputs surpass inhibitory influences and reach the threshold, an action potential is triggered.
• Spatial summation occurs when multiple synapses release neurotransmitters simultaneously, while temporal summation results from rapid, successive signals from the same synapse.
• Acting as agonists of nicotinic acetylcholine receptors (nAChRs) in the nervous systems of insects the Neonicotinoids are a class of insecticides which disrupt synaptic transmission and mimic acetylcholine, binding irreversibly to nAChRs and causing prolonged receptor activation.
• Excessive nerve firing, paralysis, and ultimately death is caused by continuous depolarization of the postsynaptic membrane.
• Neonicotinoids can also impact non-target organisms, such as pollinators like bees, by impairing their neural function, leading to disorientation, reduced foraging efficiency, and colony decline and are not easily broken down by acetylcholinesterase, prolonging their toxic effects.
• Ion channels play a crucial role in depolarization and repolarization during an action potential.
• Depolarization occurs when voltage-gated sodium (Na*) channels open in response to a stimulus, allowing Na* ions to rush into the neuron, making the inside of the cell more positive and repolarization follows as voltage-gated potassium (K+) channels open while Na* channels inactivate.
• K+ ions exit the neuron, restoring the negative resting membrane potential and driving the membrane potential toward a peak positive value once the membrane potential reaches the threshold when more Na* channels open, rapidly.
• Restoring ion balance and prepares the neuron for another action potential requires the sodium-potassium pump (Na+/K+ ATPase) which in some cases, hyperpolarization occurs due to prolonged K⁺ efflux before the neuron returns to its resting state.
• Progesterone exerts its effects on target cells by binding to intracellular progesterone receptors, which then act as transcription factors to regulate gene expression.
• Progesterone is crucial for maintaining the uterine lining, preparing it for potential embryo implantation, and inhibiting uterine contractions during pregnancy, influences the hypothalamus and pituitary gland, suppressing the release of gonadotropins to prevent ovulation during pregnancy and stimulates the development of milk-producing structures in mammary gland cells and affects smooth muscle cells by relaxing the uterine and gastrointestinal muscles, which can slow digestion.
• Acetylcholine receptor (AChR) is a classic example of a ligand-gated ion channel that alters membrane potential in response to neurotransmitter binding.
• Muscarinic AChRs indirectly influence membrane potential by activating intracellular signaling pathways that regulate ion channels and the binding of acetylcholine (ACh) to nicotinic AChRs on the postsynaptic membrane, causes a conformational change that opens the receptor's ion channel whereas acetylcholine (ACh) is released into the synaptic cleft.
• Activation mechanisms, and types of signaling molecules vary between transmembrane receptors in the plasma membrane and intracellular receptors.
• Upon activation, these receptors trigger intracellular signaling cascades that alter cell function and transmembrane receptors, such as G-protein-coupled receptors and ligand-gated ion channels, are embedded in the cell membrane and bind hydrophilic signaling molecules, like neurotransmitters and peptide hormones.
• Intracellular receptors often act as transcription factors, directly regulating gene expression by binding to DNA and bind hydrophobic signaling molecules, such as steroid hormones, that diffuse through the cell membrane.
• Transmembrane receptors mediate rapid, short-term cellular responses, intracellular receptors typically induce longer-lasting changes by modifying gene transcription.
• Quorum sensing is a bacterial communication process that allows populations to coordinate gene expression based on cell density.
• Bioluminescence is regulated by quorum sensing through the production and detection of signaling molecules called acyl-homoserine lactones (AHLs) in Vibrio fischeri, a marine bacterium.
• AHLs diffuse away, and bioluminescence genes remain inactive at low cell densities and AHLs accumulate and bind to the LuxR transcriptional regulator, activating the lux operon, which encodes enzymes like luciferase responsible for light production as the bacterial population grows.
• Vibrio fischeri exhibits this behavior in symbiosis with the Hawaiian bobtail squid, providing camouflage by mimicking moonlight in exchange for nutrients.

Test your understanding of cell signaling pathways, including GPCRs, second messengers, and their effects on cellular function. Explore renal physiology concepts such as urine concentration, ion transport, and the impact of various drugs on these processes.