Porth's Essentials of Pathophysiology, 4e

12

Cell and Tissue Function

U N I T 1

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Hormone (First messenger)

Integration of Cell Function Within a complex organism, such as a human being, dif- ferent organs, tissues, and individual cell types develop spe- cialized functions and needs. Yet each cell must contribute to the integrated life process as the body grows, differenti- ates, and adapts to changing conditions. Such integration requires that cells have the ability to communicate with one another, transport substances between their intracellular and extracellular environments, and generate and respond to changes in the electrical charge of membrane potentials. Signaling systems consist of receptors that reside either on the cell membrane (surface receptors) or within the cells (intracellular receptors). Receptors are activated by a variety of chemical messengers including neurotrans- mitters, hormones, growth factors, and other chemical messengers, as well as signaling proteins called cyto- kines and lipids . Some lipid-soluble chemical messengers move through the membrane and bind to cytoplasmic or nuclear receptors to exert their physiologic effects. Signaling systems often rely on the intermediary activity of a separate class of membrane-bound regulatory pro- teins to convert extracellular signals, or first messengers, into intracellular signals, or second messengers, such as a unique form of adenosine monophosphate called cyclic adenosine monophosphate (cAMP). Many mol- ecules involved in signal transduction within cells are enzymes and other proteins. Some of the enzymes are protein kinases that catalyze the phosphorylation of proteins, thereby changing their activity and function. Cell Surface Receptors Each cell type in the body contains numerous receptor proteins, which as a set may characterize the cell type, that enable it to respond to a complementary set of ligands (i.e., molecules with a high affinity for a recep- tor) or signaling molecules in a specific, preprogrammed way. These receptors, which span the cell membrane, relay information to a series of intracellular interme- diates that eventually pass the signal to its final des- tination. There are three major classes of cell surface receptor proteins: G protein–linked receptors, enzyme- linked receptors, and ion channel–linked receptors. G Protein–Linked Receptors. G protein–linked recep- tors mediate cellular responses for numerous types of first messengers through regulatory proteins called G proteins that bind to guanine nucleotides such as guanine diphosphate (GDP) and guanine triphosphate (GTP). With more than 1000 members, G protein–linked recep- tors are the largest family of cell surface receptors. Although there are differences among the G protein– linked receptors, all share a number of features. They all have a ligand-binding extracellular receptor component, Cell Signaling and Communication Mechanisms

Amplifier Enzyme

Extracellular fluid

Adenyl cyclase

Receptor

Intracellular fluid

G protein (Transducer)

Phosphorylated precursor

Second messenger

cAMP

ATP

Intracellular effector

Cell response

which recognizes a specific ligand or first messenger. Upon ligand-binding, they all undergo conformational changes that activate the G protein found on the cytoplasmic side of the cell membrane (Fig. 1-9). All G proteins incorpo- rate the guanosine triphosphatase (GTPase) cycle , which functions as a molecular switch that exists in two states: an activated (on) state and an inactivated (off) state. Receptor activation causes the α subunit to dissociate from the receptor and the β and γ subunits and transmit the signal from the first messenger to a membrane-bound intermediate called an effector . Often, the effector is an enzyme that converts an inactive precursor molecule into a second messenger, which diffuses into the cytoplasm and carries the signal beyond the cell membrane. One com- mon effector is the enzyme adenylyl cyclase , which con- verts the precursor ATP to the second messenger cAMP, transferring the two phosphate groups to other proteins. This transfer changes the conformation and function of these proteins. Such changes eventually produce the cell response initiated by the first messenger, whether it is a secretion, muscle contraction or relaxation, or change in metabolism. Sometimes it is the opening of membrane channels involved in calcium or potassium influx. FIGURE 1-9. Activation of a G-protein-linked receptor and production of cyclic adenosine monophosphate (cAMP). Binding of a hormone (the first messenger) causes the activated receptor to interact with the inactive, guanine diphosphate (GDP)-bound G protein.This results in activation of the G protein and dissociation of the G protein α , β , and γ subunits.The activated α subunit of the G protein can then interact with and activate the membrane protein adenyl cyclase to catalyze the conversion of adenosine triphosphate (ATP) to the second messenger cAMP. The second messenger then activates an internal effector, which leads to the cell response.

Enzyme-Linked Receptors. Like G protein–linked receptors, enzyme-linked receptors are transmembrane