2.2.1 General Physiology

Foundations of General Physiology 🧬

General physiology is the study of how cells and tissues work at the most basic functional level. In USMLE Step 1, this chapter connects the molecular world from biochemistry and cell biology with the organ systems you will study later. Here you focus on fundamental principles that apply to all cells, regardless of their specific tissue or organ.

General physiology deals with how the body maintains internal constancy, how substances move across membranes, how cells communicate, and how excitable tissues like nerve and muscle generate and conduct signals. The goal is to understand the “rules of operation” that every system must follow.

Homeostasis and Control Systems 🧭

One of the central concepts is homeostasis. The body must keep key variables such as temperature, blood glucose, pH, and osmolarity within a narrow range in order for enzymes and cells to function properly. Disturbances of homeostasis are a common source of disease and are frequently tested.

The body achieves homeostasis using control systems. A typical control system has a variable, such as blood pressure, a sensor that detects changes in that variable, an integrating center that compares the sensed value to a set point, and effectors that act to restore the set point. In physiology, the integrating center is usually the central nervous system or endocrine organs.

Negative feedback is the standard mechanism the body uses to stabilize variables. When a variable deviates from its set point, negative feedback responses act to oppose the change and bring the variable back. For example, an increase in blood glucose after a meal stimulates insulin release, which lowers blood glucose toward normal. Positive feedback, in contrast, amplifies a change. It is uncommon but important in specific contexts such as the upstroke of the action potential or oxytocin release during labor. Positive feedback usually requires an external mechanism or eventual negative feedback to terminate the response.

Time is also important in control systems. The speed of response can differentiate nervous system control, which is rapid and often transient, from endocrine control, which is slower but has more sustained effects. Anticipatory, or feedforward, mechanisms adjust function in advance of a predicted change, such as increased heart rate before exercise begins.

Body Fluid Compartments and Osmolarity 💧

A core topic in general physiology is how water and solutes are distributed in the body. Total body water is divided into intracellular fluid and extracellular fluid. Intracellular fluid is the water inside cells. Extracellular fluid is outside cells and is further divided into interstitial fluid around cells and plasma within blood vessels. These compartments are separated by physical barriers such as cell membranes and capillary walls, each with characteristic permeability to water and solutes.

Although each compartment differs in solute composition, the overall osmolarity is normally the same in all compartments at steady state. Osmolarity describes the concentration of solute particles per liter of solution. It is closely related to tonicity, which refers to the effective osmotic pressure that causes water movement across cell membranes. A solution that causes cells to swell is hypotonic, one that causes cells to shrink is hypertonic, and one that leaves cell volume unchanged is isotonic.

The movement of water between compartments depends on solute content. Adding isotonic saline to the extracellular compartment expands extracellular volume but does not change osmolarity, so water does not need to shift into or out of cells. Adding pure water lowers extracellular osmolarity and water moves into cells, increasing intracellular volume. Understanding these shifts is critical for interpreting volume status and for predicting the effects of intravenous fluids in clinical scenarios.

Cell Membranes and Transport Mechanisms 🚪

General physiology also focuses on how substances cross cell membranes. The plasma membrane is a selective barrier that permits some substances to pass easily while restricting others. Different types of transport make this possible.

Simple diffusion allows small, nonpolar molecules such as oxygen and carbon dioxide to move directly through the lipid bilayer from high to low concentration. This movement is passive and does not require energy. Facilitated diffusion also moves substances down their electrochemical gradient but uses membrane proteins such as channels or carriers. Transport by channels is rapid and typically limited by the open probability of the channel. Carrier mediated transport can reach a maximal rate, called $V_{max}$, as all carriers become saturated.

Primary active transport uses energy directly from ATP hydrolysis to move solutes against their gradient. A key example is the sodium potassium ATPase, which exports sodium from the cell and imports potassium. Secondary active transport uses energy stored in an existing gradient, usually the sodium gradient generated by the sodium pump, to move another solute. Cotransporters move solutes in the same direction, while exchangers or antiporters move solutes in opposite directions. Osmosis is the passive movement of water across a semipermeable membrane down its own concentration gradient, which is usually equivalent to moving toward higher solute concentration.

A useful summary is shown below.

Resting Membrane Potential and Ion Gradients ⚡

Excitable tissues such as neurons and muscle cells rely on differences in ion concentration across the membrane. General physiology introduces the idea that the cell interior is usually negative relative to the outside. This voltage difference is the resting membrane potential. It arises from unequal ion distribution, selective permeability to some ions more than others, and the activity of transporters such as the sodium potassium ATPase.

Potassium is usually more concentrated inside the cell, while sodium, chloride, and calcium are more concentrated outside. Because many cells are more permeable to potassium at rest, the resting potential lies near the potassium equilibrium potential. The equilibrium potential for each ion is the membrane voltage at which there is no net flux of that ion. It depends on the ratio of outside to inside concentrations and is described mathematically by an exponential relationship.

When multiple ions contribute to the membrane potential, a more complete description includes the relative permeabilities of each ion. Changes in permeability to a given ion can depolarize the membrane by making the inside less negative, or hyperpolarize it by making it more negative. These changes are the foundation for signaling in nervous and muscle tissue and are explored in depth when you study specific excitable organs.

Receptors, Signal Transduction, and Second Messengers 📡

Cells must detect and respond to signals from other cells and from the environment. In general physiology, this process is called signal transduction. A chemical messenger binds to a receptor, which triggers intracellular events that change cell function. Receptors may be on the cell surface or inside the cell depending on the solubility of the messenger.

Hydrophilic messengers such as peptide hormones usually bind to transmembrane receptors on the cell surface. These receptors often activate intracellular signaling cascades using second messengers like cyclic AMP, inositol triphosphate, diacylglycerol, or calcium. Hydrophobic messengers, such as steroid hormones, usually cross the membrane and bind intracellular receptors that often act as transcription factors to regulate gene expression.

Receptors fall into several major families. G protein coupled receptors are very common and activate different second messenger pathways depending on the G protein subtype. Enzyme linked receptors, such as receptor tyrosine kinases, have intrinsic catalytic domains and can directly phosphorylate targets. Ligand gated ion channels open or close to alter ion flow when they bind their ligand. Intracellular receptors in the cytoplasm or nucleus interact with DNA to change transcription.

Signaling pathways often amplify the initial signal so that a small number of ligand molecules can cause a large cellular response. They can also be modulated at many points, which allows fine control and provides many pharmacologic targets.

Excitable Tissues and Action Potentials ⚙️

General physiology introduces the basic features of how excitable cells generate rapid electrical signals called action potentials. These signals occur in neurons, skeletal muscle, cardiac muscle, and some smooth muscle. Action potentials are stereotyped changes in membrane potential that are propagated along the membrane without decrement.

An action potential is usually triggered when depolarization reaches a threshold. At threshold, voltage gated sodium channels open rapidly, which causes a large influx of sodium and a rapid depolarization. These channels then inactivate, and voltage gated potassium channels open, allowing potassium efflux and repolarization of the membrane back toward the resting potential. Some cells have additional channel types or phases, and action potential shapes differ between tissues, but the core principle is the same.

Action potentials are all or none events. Once threshold is reached, the amplitude and time course of the action potential in a given cell type are relatively constant. During the absolute refractory period, another action potential cannot be generated regardless of stimulus strength because sodium channels are inactivated. During the relative refractory period, a stronger than usual stimulus is required because some channels are still recovering and the membrane may be hyperpolarized.

Propagation of the action potential along an axon depends on passive current spread and regeneration by voltage gated channels. Myelination increases conduction velocity and efficiency by insulating the axon and allowing the action potential to jump between nodes of Ranvier, a process called saltatory conduction.

Synaptic Transmission and Neuromuscular Principles 🧩

Once action potentials arrive at the end of a neuron, they must be converted into signals that can pass to another cell. In chemical synapses, depolarization of the presynaptic terminal opens voltage gated calcium channels. Calcium entry triggers fusion of synaptic vesicles with the membrane and release of neurotransmitter into the synaptic cleft. The neurotransmitter diffuses across and binds to receptors on the postsynaptic membrane, which can be ligand gated ion channels or G protein coupled receptors.

The postsynaptic response depends on which receptors are present. Some synapses are excitatory and depolarize the postsynaptic cell. Others are inhibitory and hyperpolarize it or make it less likely to fire by increasing membrane conductance to ions like chloride or potassium. The postsynaptic cell integrates all of its excitatory and inhibitory inputs in time and space to decide whether to generate an action potential. This integration is a key principle throughout the nervous system and is foundational for later neurology and psychiatry topics.

At the neuromuscular junction, a specialized synapse between a motor neuron and skeletal muscle fiber, similar principles apply but the details are adapted for rapid and reliable activation of muscle contraction. The neurotransmitter is released in discrete packets, and binding on the muscle side produces a depolarizing end plate potential. If this potential reaches threshold, it triggers an action potential in the muscle fiber, which then initiates contraction.

Acid Base and Basic pH Concepts 🧪

General physiology introduces broad ideas about how the body controls hydrogen ion concentration. The pH of the extracellular fluid must remain within a narrow range so that proteins maintain their structure and function. The logarithmic nature of the pH scale means that small numeric changes reflect substantial shifts in hydrogen ion concentration.

Buffers are pairs of weak acids and their conjugate bases that resist changes in pH when small amounts of acid or base are added. In physiology, the bicarbonate buffer system is dominant in extracellular fluid. Ventilation and renal function together help maintain proper pH by adjusting carbon dioxide and bicarbonate levels. You will study the mechanisms in detail in respiratory and renal physiology, but here you should appreciate that maintaining pH is a continual dynamic process.

A key relationship connects pH to the ratio of base to acid in a buffer system. This relationship explains why changes in either component can alter pH and why the body can compensate for a primary disturbance in one variable by adjusting the other.

Temperature Regulation and Basal Metabolism 🌡️

General physiology also outlines how the body manages its temperature. Humans maintain a relatively constant internal temperature despite changes in environmental conditions and metabolic activity. This is important because most enzymes and cellular processes function optimally within a narrow temperature range.

Heat is produced by basal metabolic processes, muscular activity, and hormonal influences. It is lost through radiation, conduction, convection, and evaporation. The hypothalamus serves as an integrating center for temperature regulation. It compares input from temperature sensors to a set point and initiates responses such as sweating, vasodilation of skin vessels, shivering, or behavioral changes.

Alterations in the set point or the balance between heat production and heat loss result in fever, hyperthermia, or hypothermia. Fever involves an upward shift in the hypothalamic set point, triggered by mediators such as prostaglandins in response to infection or inflammation. In contrast, hyperthermia arises when heat production or environmental load overwhelms the body’s capacity for heat loss without a set point change.