WK 8_CELLULAR COMMUNICATION.pdf

BIOCHEMISTRY st 1 Year | A.Y. 2024-2025 CELL COMMUNICATION Lecturer: Denzy Rose Tangkusan, MD CELLULAR COMMUNICATION / CELL SIGNALING how cells communicate with one another cell-to-cell signaling cell communication HOW DO CELLS COMMUNIC...

BIOCHEMISTRY st 1 Year | A.Y. 2024-2025 CELL COMMUNICATION Lecturer: Denzy Rose Tangkusan, MD CELLULAR COMMUNICATION / CELL SIGNALING how cells communicate with one another cell-to-cell signaling cell communication HOW DO CELLS COMMUNICATE? Communication components 1. Sender 2. Messenger 3. Receiver 4. Effecter Sender cell: sends signals in the form of signaling molecules or ligands (e.g. hormones, neurotransmitters, chemical messenger) Signal molecules: can travel from short distances to very long distances, and when it reaches the receiving cell, there is a receptor (e.g. plasma membrane, cytoplasm, nucleus) that is activated. Once the signal is received, there is a physiological effect 2. Paracrine signaling - the sender cell releases the signal in the or response. extracellular fluid and the chemical messenger travels very short distances such that the chemical messenger would be able to travel SIGNALING MOLECULES to the neighboring or adjacent cells. 1. Cell-to-cell contact or lose proximity- the signal is immediately passed on the receiving cell 2. Long or short distances Ligand- this is a molecule that specifically binds to a receptor, resulting in a physiologic effect. Hormones Insulin Gastrin Growth Hormone Neurotransmitters Acetylcholine Norepinephrine Serotonin Nitric Oxide Polar Ligands Peptides (water-soluble/hydrophilic) Amino acids Non-polar Ligands Steroid hormones (hydrophobic/lipophilic) Thyroid hormones Vitamins A and D MECHANISM OF CELL TO CELL COMMUNICATION 1. Contact dependent or Direct contact - close proximity (gap junction), there is direct contact between the sender cell and the receiving cell. Gap Junction - tunnel between two cells to have direct contact (e.g. chemical messengers) Biochemistry | Week 8 Ferviente 2028 BIOCHEMISTRY st 1 Year | A.Y. 2024-2025 CELL COMMUNICATION Lecturer: Denzy Rose Tangkusan, MD 3. Autocrine - “auto” wherein the sender cell is also the receiving cell - intracrine signaling: - “inside the cell” - The chemical messenger is not released into the EDF but rather stays inside and activates a receptor. GENERAL SCHEME OF BINDING TO A RECEPTOR 4. Synaptic - Similar to Paracrine signaling, however, this only occurs between nerve-nerve or nerve-another cell. 1. Process of recognition: The ligand reachers the target cell and binds to a receptor. 2. Signal Transduction: The signal from outside is transmitted 5. Endocrine Signaling intracellularly. - the chemical messenger travels through the blood vessels 3. Activation of several Effector Proteins: there will be (long distance) until it reaches the target cells. modulation of the signal (the signal becomes stronger) 4. Different Physiological events are reached, which are either metabolic or mitogenic (affects the growth and differentiation of the cell. Biochemistry | Week 8 Ferviente 2028 BIOCHEMISTRY st 1 Year | A.Y. 2024-2025 CELL COMMUNICATION Lecturer: Denzy Rose Tangkusan, MD Biochemistry | Week 8 Ferviente 2028 BIOCHEMISTRY st 1 Year | A.Y. 2024-2025 CELL COMMUNICATION Lecturer: Denzy Rose Tangkusan, MD Modulation: A single ligand wound activates a lot of effector proteins resulting in a modulated/more intense/amplified physiologic effect. TYPES OF RECEPTORS When the binding site for acetylcholine is not occupied by the acetylcholine, the ion channel is closed. But when acetylcholine attaches to the binding site, the ion channel would open up. So when the ion channels open up, the ions specific to that channel would enter. An example is a sodium channel that is ligand-gated. In other words, when it opens up, the sodium ions can enter. The same way, when the acetylcholine is removed or detached from the binding site, the ion channels would close. B. G Protein Coupled Receptors Also known as the “7 Transmembrane Domain Receptors or Serpentine Receptors” Most common receptor PLASMA MEMBRANES RECEPTORS Found on plasma membrane Activated by polar ligands (Polar substances cannot readily pass through the cell) A. Ion Channel Receptors Also known as “Ligand-gated Ion Channels” Note: 7 transmembrane because it crosses the plasma membrane Mediate direct and Rapid Signaling seven times and serpentine because it’s like a snake. Then it has extracellular leaf and intracellular leaf. Biochemistry | Week 8 Ferviente 2028 BIOCHEMISTRY st 1 Year | A.Y. 2024-2025 CELL COMMUNICATION Lecturer: Denzy Rose Tangkusan, MD The extracellular leaf is the one that acts as the receptor or the one that recognizes the ligand. The intracellular leaf is where the G protein binds to. That’s why it is called a G protein coupled, a G protein is coupled to this receptor. Physiologic response is mediated by G proteins, attached to the receptor itself GRPn0 effect GNO effect ⑧ o Biochemistry | Week 8 Ferviente 2028 BIOCHEMISTRY st 1 Year | A.Y. 2024-2025 CELL COMMUNICATION Lecturer: Denzy Rose Tangkusan, MD - The protein kinase A can attach a phosphate to other proteins or enzymes thereby activating or inhibiting the protein/ enzyme. This depends on what signal and what type of cell is being activated by that ligand. The main point is when your protein kinase is activated it can phosphorylate another enzyme which can either activate or inactivate other metabolic pathways. 2. Phosphodiesterase Pathway- activated by G (G protein with a subunit) -shown in the figure below is an example of phosphodiesterase pathway which is the G protein, specifically the Transducin Gt 1. Cyclic nucleotide- cAMP and cGMP which is found in the photoreceptor in our eyes. 2. Phosphoinositide (PIP2) products- IP3 and DAG 3. Calcium 4. Arachidonic acid metabolites- prostaglandins, thromboxanes, leukotrienes, HETE, EET The types of secondary messenger depend on which signal transduction pathway: 1. Adenyl Cyclase/ cAMP/ Protein kinase A Pathway- activated by G protein/ Gs (S stands for stimulatory). It is inhibited when another set of G protein coupled receptor is activated which are the GI (I stands for inhibitory). - when PKA is activated, it can open up to L-type calcium channels. Aside from that, it can also do a lot of things. One of which is that it can activate certain enzymes. - The figure below shows how protein kinase A is activated by cAMP. Biochemistry | Week 8 Ferviente 2028 BIOCHEMISTRY st 1 Year | A.Y. 2024-2025 CELL COMMUNICATION Lecturer: Denzy Rose Tangkusan, MD 3. Phospholipases- these are enzymes that would hydrolyze the phospholipid. Shown in the figure below are different types of Phospholipases (A1, A2, C and D). Among the phospholipases A2 and C are the most common. 4. Calcium- secondary messenger; can either be increased by Gs, or Phospholipase C pathway/ inositol triphosphate - Gs directly stimulated certain ion channel *e.g. L-type Ca2+ channels) - Phospholipases C would produce diacylglycerol and - Gs also indirectly stimulates via PKA pathway Inositol triphosphate. Phospholipase C is activated by a ② Gq - Gs Physiologic response is mediated by Calcium- Calmoudin - Phospholipase A2 would specifically release arachidonic complex (e..g contraction of muscle) acid which is an important precursor of inflammatory - Calcium does not directly cause the physiologic substances known as prostaglandins and leukotrienes. effect but rather it is because of Calcium- Phospholipase A2 is mediated by eitherooGi or Go Calmoudin Complex Figure is an example of how stimulatory G-protein works. Biochemistry | Week 8 Ferviente 2028 BIOCHEMISTRY st 1 Year | A.Y. 2024-2025 CELL COMMUNICATION Lecturer: Denzy Rose Tangkusan, MD Steps that produce CO2 The following would be encountered again in Autonomic Nervous System, the different receptors, ligands, examples, and effects Additional information/Subtopic activating these special types of receptors: More additional information The Calcium-Calmodulin Complex can activate certain enzymes c. Enzyme-linked Receptors - third type of plasma receptor. Different from GPCRS 5. Other signaling pathways associated with G proteins because in this set of receptors, there is an inherent, in the intracellular side there is an enzyme or catalytic domain, a A. Protein phosphatases certain part of that receptor is an enzyme. - Remove phosphates on certain enzymes. The results can either be activating or inhibiting that specific enzyme. B. By subunit from G-protein - part of the heterotrimeric G protein; implicated in " receptor desensitization" (or down regulation of the receptor) - - prolonged increase or activation of the receptor, with lots of ẞ y subunit, this will result or cause a decrease in the number the receptors present on the plasma membrane (it is like a feedback regulatory mechanism) C. Monomeric G proteins - depends on GTP binding; regulated by GAPS and GEFs - The G-protein attached to GPC are single unit Examples of Monomeric G-protein and their respective involvement/ 1. Guanylyl cyclase receptor function: - When the ligand activates the receptor, the guanylyl cyclase would become activated thereby converting the GTP into cyclic GMP (cGMP), which in turn results to the physiologic response. - It is similar to adenylyl cyclase but instead of using ATP, it involves GTP. Biochemistry | Week 8 Ferviente 2028 BIOCHEMISTRY st 1 Year | A.Y. 2024-2025 CELL COMMUNICATION Lecturer: Denzy Rose Tangkusan, MD 2. Serine/ threonine kinase receptor - It would activate or phosphorylate the specific serine and threonine domains of certain proteins including its own domain, there will be autophosphorylation for this receptor. 3. Tyrosine kinase receptor - Example of whole/ tetrameric form, not fusing together - more common catalytic receptor is the Receptor Tyrosine Kinase (RTK) 2 types: Monomeric & Dimeric - Will become homotetrameric RTK Figure is an example of monomeric (1) separated ligand, (2) ligand that binds to each units forming a dimer (dimerization), (3) upon dimerization there will be autophosphorylation, the tyrosine kinase domain will phosphorylate the other part vice versa, (4) complete or Example: Insulin receptor (tetrameric receptor tyrosine kinase), activated tyrosine kinase domain, which could activate other effector when insulin binds to it there is autophosphorylation but without proteins. dimerization, thus it could phosphorylate the other effector proteins such as Pi3K, Grb SOS, & Insulin Receptor Substrate (IRS). 4. Tyrosine Kinase-Associated receptor - The receptor does not have an inherent tyrosine kinase activity, but rather merong nakadikit sa kanya which is what we call JAK or the Janus Kinase family (Old name: Just Another Kinase). These are your tyrosine Kinases. When the ligand binds to it, the JAK would phosphorylate the receptor. After phosphorylation, another factor Biochemistry | Week 8 Ferviente 2028 BIOCHEMISTRY st 1 Year | A.Y. 2024-2025 CELL COMMUNICATION Lecturer: Denzy Rose Tangkusan, MD would bind to it which is the STAT (starts the Transcription of the It can be mediated by: mRNA). 1. Steroid and thyroid hormones - through intracellular The STAT together with phosphate will dimerize and receptors (either cytoplasmic or nuclear receptors) enter the nucleus, starting the Transcription. 2. cAMP - through cAMP-response element binding proteins (CREBS} 3. Receptor tyrosine kinases - through monomeric G proteins and mitogen-activated protein kinase (MAPK) 4. Tyrosine kinase-associated receptors - through Janus kinases (JAK) and signal transducers and activators of transcription (STAT). INTRACELLULAR RECEPTORS REGULATED INTRAMEMBRANE PROTEOLYSIS (RIP) Once inside the cell, it can now bind to its receptor. The hormone plus the receptor will form a complex and enter the nucleus, thereby - Not a classical type of signaling mechanism starting the transcription process (DNA to mRNA). The mRNA would - Membrane proteins that do not fit the classic definition of dictate the sequence of amino acids through protein synthesis. The a receptor. protein produced can either be an enzyme or a channel resulting in a - Able to recognize extracellular signal - translate into an physiologic effect. intracellular effect. Summary Speakers Note: A membrane protein upon which if there is a signal, the membrane protein will be cut off. The part then enters the Differentiated the: Transcription. 1. Mechanisms of cell-to-cell communication. 2. Types of ligands. 3. Classes of receptors based on location and mechanism. A. Plasma receptors - lon channel receptors - GPCRs - Catalytic receptors B. Intracellular receptors Ayura lecture link: https://www.youtube.com/watch?v=aqvA1KLU-i8 vid ni doc Jacinto REGULATION OF GENE EXPRESSION Speaker’s Note: As I’ve said earlier, the effects of signal Transduction mechanisms can affect the metabolism of the cell, and the other one would be the growth of the cell. In terms of growth, most of the time, it involves regulation of Gene Expression. Biochemistry | Week 8 Ferviente 2028