《医学生理学 Medical Physiology》参考教材资料（PDF电子书籍）USMLE Road Map - Physiology

4 USMLE Road Map: Physiology 5. Primary active transport is the transport of a substrate across the plasma membrane against its concentration gradient. It requires the input of cellu- ergy in the form of ATP. a. Proteins that mediate primary active transport are known as pumps, which strates against their concentration gradient. b. The best-studied example of primary active transport is the Na' /K'* ATPase, a Na /K pump. The Na'/K-ATPase generates low extracellular K and high llular na concentrations c. Another example of primary active transport is Ca-ATPase, which clears Ca from the cytoplasm. Such Ca pumps are found on both the plasma and endoplasmic reticulum(Er) membranes. 6. Coupled transport, or secondary active transport, uses the energy of ionic ually Na, across the plasma memb a. Coupled transport still carries substrates against their concentration gradi- ent, but transport is provided indirectly from the energy stored in the con- centration gradient of an additional ion transported in the same cycle. b. For example, in a Na-coupled transporter system, Na' concentration is higher in the extracellular space than in the cytoplasm. Therefore, Na movement into the cytosol is energetically favored c. Coupled transport systems are divided into two groups: Cotransporters (also called symporters)move solutes in the same direction, and exchang ers(also called antiporters) transport solutes in opposite directions. Co- transporters and exchangers work only if both substrates are present. d. An example of a cotransporter is the Na-glucose transporter, found in the renal proximal tubule and small intestine, which allows glucose absorp- tIon. e. An example of an exchanger is the Na-Ca* exchanger found in many cell portant in regulating cytoplasmic ports three Na' in for one Ca"out, making it an electrogenic transporter. It is electrogenic because it makes a small contribution to the electrical po- tential across the membrane CARDIAC STIMULANTS The Nat pump is the target for a class of naturally occurring compounds from the wild flower Dig purpurea(foxglove). These compounds have been used for almost two centuries as cardiac stil These cardiac glycosides, including Ouabain and digitalis, inhibit the Na/K-ATPase pump IL. Ion Channels A. Ions move quickly through protein pores in biologic membranes known as ion channels B. Ions flow through these channels from one side of the membrane to the other down their electrochemical gradient C. Channel proteins display two different conformational states: open or closed D. The process that controls the transition between conformational states is called E. lon channel gating is the mechanism that controls the probability of a channel being in each of its conformational states

4 USMLE Road Map: Physiology N 5. Primary active transport is the transport of a substrate across the plasma membrane against its concentration gradient. It requires the input of cellu￾lar energy in the form of ATP. a. Proteins that mediate primary active transport are known as pumps, which use the energy derived from ATP hydrolysis to power the transport of sub￾strates against their concentration gradient. b. The best-studied example of primary active transport is the Na+ /K+ - ATPase, a Na+ /K+ pump. The Na+ /K+ -ATPase generates low extracellular K+ and high intracellular Na+ concentrations. c. Another example of primary active transport is Ca2+-ATPase, which clears Ca2+ from the cytoplasm. Such Ca2+ pumps are found on both the plasma and endoplasmic reticulum (ER) membranes. 6. Coupled transport, or secondary active transport, uses the energy of ionic gradients, usually Na+ , across the plasma membrane. a. Coupled transport still carries substrates against their concentration gradi￾ent, but transport is provided indirectly from the energy stored in the con￾centration gradient of an additional ion transported in the same cycle. b. For example, in a Na+ -coupled transporter system, Na+ concentration is higher in the extracellular space than in the cytoplasm. Therefore, Na+ movement into the cytosol is energetically favored. c. Coupled transport systems are divided into two groups: Cotransporters (also called symporters) move solutes in the same direction, and exchang￾ers (also called antiporters) transport solutes in opposite directions. Co￾transporters and exchangers work only if both substrates are present. d. An example of a cotransporter is the Na+ -glucose transporter, found in the renal proximal tubule and small intestine, which allows glucose absorp￾tion. e. An example of an exchanger is the Na+ -Ca2+ exchanger found in many cell types and important in regulating cytoplasmic Ca2+. The exchanger trans￾ports three Na+ in for one Ca2+ out, making it an electrogenic transporter. It is electrogenic because it makes a small contribution to the electrical po￾tential across the membrane. CARDIAC STIMULANTS • The Na+ pump is the target for a class of naturally occurring compounds from the wild flower Digitalis purpurea (foxglove). These compounds have been used for almost two centuries as cardiac stimulants. • These cardiac glycosides, including Ouabain and digitalis, inhibit the Na+ /K+ -ATPase pump. II. Ion Channels A. Ions move quickly through protein pores in biologic membranes known as ion channels. B. Ions flow through these channels from one side of the membrane to the other, down their electrochemical gradients. C. Channel proteins display two different conformational states: open or closed. D. The process that controls the transition between conformational states is called gating. E. Ion channel gating is the mechanism that controls the probability of a channel being in each of its conformational states. CLINICAL CORRELATION 5506ch01.qxd_ccII 2/17/03 2:08 PM Page 4

For example, a voltage-gated Na channel is closed at the resting membrtential 1. Voltage-activated channels are opened and closed by the membrane tential and is open only when the membrane potential is rapidly depolarized. 2. Ligand-activated channels are controlled primarily by the binding of extra ellular or intracellular ligands to the channel proteins. These channels are a. In a direct receptor channel complex, the receptor for the ligand is a di rect part of the channel protein. The nicotinic acetylcholine receptor (AchR) is an example of this type of channel. b. In an intracellular second messenger-gated channel, the binding of li- gands to receptors activates a cascade of second messenger molecules, one of which binds to the channel protein in order to control channel gating The cyclic guanosine monophosphate(cGMP)-gated channel in a pho- receptor is an exam In a direct G-protein-gated channel, the binding of a ligand to its recep tor activates a guanosine triphosphate (GTp)-binding regulatory pro tein(G-protein) that changes the conformation of the channel with rolling second messenger systems. For example, the cardiac inwardly di rected potassium channel KAch, which slows the heart after vagus nerve imulation, is gated by a G-protein F. Ion channels can select one kind of ion over another 1. Channels are often named according to the ions they prefer(eg, Na' channel K channel, and Ca channels) 2. To account for the selectivity in certain voltage-gated channels, there appear to be a narrow region in the channel pore that fits only on a particular ion G. Ion channels provide a useful target for drug action 1. Lidocaine, an antiarrhythmic drug, blocks Na' channels in a use-dependent manner 2. The higher the frequency of stimulation (ie, heart rate), the more that lide caine blocks the channel H. lon channels are affected by disease both directly and indirectly 1. Direct actions on the channel protein structure occur as a result of genetic 2. Indirect actions include abnormalities in the regulator mechanism required for channel function and in the development of autoimmune disease ON CHANNEL DISEASES Cystic fibrosis is an autosomal recessive disease that affects 1 in 2500 individuals. It is an example of a direct effect on ion channels The disease is caused by mutations in the cystic fibrosis transmembrane regulator (CTR)gene, which codes for the chloride channel gated by cyclic adenosine monophosphate( cAMP) -In most cases the deletion of a single phenylalanine molecule (pheA508) prevents the channel protein The drastic reduction in chloride channels results in thick mucous secretions that block airways, lead- ing to death in 90% of patients before they reach adulthood. Myasthenia gravis is an indirect ion channel disease produced by an autol disorder - autoantibodies against the AChRs lower the receptor concentration, causing lysis of the motor end

Chapter 1: Cell Physiology 5 N 1. Voltage-activated channels are opened and closed by the membrane potential. For example, a voltage-gated Na+ channel is closed at the resting membrane po￾tential and is open only when the membrane potential is rapidly depolarized. 2. Ligand-activated channels are controlled primarily by the binding of extra￾cellular or intracellular ligands to the channel proteins. These channels are grouped into three categories: a. In a direct receptor channel complex, the receptor for the ligand is a di￾rect part of the channel protein. The nicotinic acetylcholine receptor (AchR) is an example of this type of channel. b. In an intracellular second messenger–gated channel, the binding of li￾gands to receptors activates a cascade of second messenger molecules, one of which binds to the channel protein in order to control channel gating. The cyclic guanosine monophosphate (cGMP)–gated channel in a pho￾toreceptor is an example. c. In a direct G-protein-gated channel, the binding of a ligand to its recep￾tor activates a guanosine triphosphate (GTP)-binding regulatory pro￾tein (G-protein) that changes the conformation of the channel without involving second messenger systems. For example, the cardiac inwardly di￾rected potassium channel KAch, which slows the heart after vagus nerve stimulation, is gated by a G-protein. F. Ion channels can select one kind of ion over another. 1. Channels are often named according to the ions they prefer (eg, Na+ channel, K+ channel, and Ca2+ channels). 2. To account for the selectivity in certain voltage-gated channels, there appears to be a narrow region in the channel pore that fits only on a particular ion. G. Ion channels provide a useful target for drug action. 1. Lidocaine, an antiarrhythmic drug, blocks Na+ channels in a use-dependent manner. 2. The higher the frequency of stimulation (ie, heart rate), the more that lido￾caine blocks the channel. H. Ion channels are affected by disease both directly and indirectly. 1. Direct actions on the channel protein structure occur as a result of genetic mutations of the channel gene. 2. Indirect actions include abnormalities in the regulator mechanism required for channel function and in the development of autoimmune disease. ION CHANNEL DISEASES • Cystic fibrosis is an autosomal recessive disease that affects 1 in 2500 individuals. It is an example of a direct effect on ion channels. –The disease is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which codes for the chloride channel gated by cyclic adenosine monophosphate (cAMP). –In most cases the deletion of a single phenylalanine molecule (phe∆508) prevents the channel protein from reaching the plasma membrane. –The drastic reduction in chloride channels results in thick mucous secretions that block airways, lead￾ing to death in 90% of patients before they reach adulthood. • Myasthenia gravis is an indirect ion channel disease produced by an autoimmune disorder. –Autoantibodies against the AChRs lower the receptor concentration, causing lysis of the motor end￾plate. CLINICAL CORRELATION 5506ch01.qxd_ccII 2/17/03 2:08 PM Page 5

6 USMLE Road Map: Physiology The decreased number of nicotinic AChRs results in smaller postsynaptic responses and a tendency to block neuromuscular transmission -individuals with this disease experience weakness of skeletal muscles. . Cell volume regulation depends on the total amount of intracellular solute 1. Following cell shrinkage, mechanisms that increase solute concentration are a. This activation is achieved either by the synthesis of small organic(ie, os motically active)molecules(eg, sorbitol or taurine) or by the transport of ions inside the cell through the Na'-H' exchanger or the Na'-H*-Ch- b. Increased solute concentration inside the cell will induce water movement by osmosis, increasing cell volume 2. Alternatively, if the cell swells, transport mechanisms that extrude solutes out of the cell (eg, K.or CI channels or the K-CI cotransporter)will be activated. 3. Because of the transport mechanisms involved, cell volume regulation depends ultimately on the Naand K' ionic gradients generated by the Na'/K' pump gephanges in cellular pH can alter the conformation of proteins with ionizable egulation of cellular pH at a constant level is critical for cell function. ups(including a variety of enzymes and channels), thus affecting their 2. Transport mechanisms that carry either H'or HCO,(bicarbonate)are portant for the maintenance of cellular PH. Transporters include the Na-H changer, which alkalinizes the cytosol, and the K-H exchanger in corneal epithelium, which acidifies the cytoplasm. K. Epithelia are sheets of specialized cells that link the body to the external environ- Epithelia are polarized at the structural, biochemical, and functional I means that one side of the epithelial sheet contains different components and possesses different properties from the other side. The side of the cell fac- ing the lumen is called the apical side, and the opposite side is the basolateral 2. Transepithelial transport can be in the form of either secretion or absorp NAw吗 y)or by moving between cels(paracellular pathway) cross an epithelial cell layer by moving through the cells (transcellular Epithelia are classified as tight or leaky based on the permeability of the para cellular pathway to ions 3. To understand how absorption through an epithelial cell layer occurs, con- ider the example of a Nacl-absorbing epithelium in the small intestine. a. The primary Na entry pathway is on the apical side and varies with the tis- sue. It can be either a Nat channel ransporter such as the Na-Hex Na-coupled cotransporters(eg, Na-glucose, Na-amino acid) Na channels on the apical membrane are members of the amiloride- sensitive Na-channel famil b. Na' efflux across the basolateral membrane is performed by the na pump. Therefore, Na' enters at the apical side and is secreted at the lateral side, resulting in net transport of Na across the epithelium C. CI- follows Na*movement across the epithelium through either the trans- cellular or the paracellular pathway, depending on the tissue

6 USMLE Road Map: Physiology N –The decreased number of nicotinic AChRs results in smaller postsynaptic responses and a tendency to block neuromuscular transmission. –Individuals with this disease experience weakness of skeletal muscles. I. Cell volume regulation depends on the total amount of intracellular solute. 1. Following cell shrinkage, mechanisms that increase solute concentration are activated. a. This activation is achieved either by the synthesis of small organic (ie, os￾motically active) molecules (eg, sorbitol or taurine) or by the transport of ions inside the cell through the Na+ -H+ exchanger or the Na+ -H+ -Cl− co￾transporter. b. Increased solute concentration inside the cell will induce water movement by osmosis, increasing cell volume. 2. Alternatively, if the cell swells, transport mechanisms that extrude solutes out of the cell (eg, K+ or Cl channels or the K+ -Cl cotransporter) will be activated. 3. Because of the transport mechanisms involved, cell volume regulation depends ultimately on the Na+ and K+ ionic gradients generated by the Na+ /K+ pump. J. Regulation of cellular pH at a constant level is critical for cell function. 1. Changes in cellular pH can alter the conformation of proteins with ionizable groups (including a variety of enzymes and channels), thus affecting their function. 2. Transport mechanisms that carry either H+ or HCO3 − (bicarbonate) are im￾portant for the maintenance of cellular pH. Transporters include the Na+ -H+ exchanger, which alkalinizes the cytosol, and the K+ -H+ exchanger in corneal epithelium, which acidifies the cytoplasm. K. Epithelia are sheets of specialized cells that link the body to the external environ￾ment. 1. Epithelia are polarized at the structural, biochemical, and functional levels. This means that one side of the epithelial sheet contains different components and possesses different properties from the other side. The side of the cell fac￾ing the lumen is called the apical side, and the opposite side is the basolateral side. 2. Transepithelial transport can be in the form of either secretion or absorp￾tion. Solutes can cross an epithelial cell layer by moving through the cells (transcellular pathway) or by moving between cells (paracellular pathway). Epithelia are classified as tight or leaky based on the permeability of the para￾cellular pathway to ions. 3. To understand how absorption through an epithelial cell layer occurs, con￾sider the example of a NaCl-absorbing epithelium in the small intestine. a. The primary Na+ entry pathway is on the apical side and varies with the tis￾sue. It can be either a Na+ channel or a transporter such as the Na+ -H+ ex￾changer or Na+ -coupled cotransporters (eg, Na-glucose, Na–amino acid). Na+ channels on the apical membrane are members of the amiloride￾sensitive Na+ -channel family. b. Na+ efflux across the basolateral membrane is performed by the Na+ /K+ pump. Therefore, Na+ enters at the apical side and is secreted at the baso￾lateral side, resulting in net transport of Na+ across the epithelium. c. Cl follows Na+ movement across the epithelium through either the trans￾cellular or the paracellular pathway, depending on the tissue. 5506ch01.qxd_ccII 2/17/03 2:08 PM Page 6

(1) The transcellular pathway refers to ion movement through the cell layer, whereas the paracellular pathway refers to ion movement be cells (2)The driving force for Cl movement through the paracellular pathway tive on the basolateral Cial generated by the net movement of Na(p is the electrical potential 3)Alternatively, if Cl crosses the epithelium through the transcellular pathway, it usually enters at the apical side through transporters(eg, CI-HCO3 exchanger, Na-K -2CI cotransporter) and leaves the cell at the basolateral side through CI" channels or the K-CI cotran- d. The activity of the Na /K-ATPase on the basolateral side will result in the ransport of k ions inside the cell. Therefore, to maintain steady-state ion concentration in the cytosol, the cell must have a mechanism to recycle the umped K*. This mechanism involves a variety of k' channels located on e basolateral membrane 4. Secretion is conceptually more difficult than absorption, but the same princi- ples discussed for absorption apply The Na'/K'-ATPase on the basolateral membrane pumps Na'out and K' into the cell. K' is recycled back into the extracellular fluid through the tion of k channels on the basolateral membran b. The Na' gradient generated by the Na'/K-ATPase is used to drive the Na-K-2Cl(or K-CI) cotransporter or sulting in the net transport of Cr into the cell c. The increased CI concentration inside the cell causes cr secretion through Cr channels on the apical membrane, resulting in net Cr trans- port across the epithelial cell layer d. The combined secretion of CI- into the lumen(apical side)and efflux ofK through K' channels on the basolateral membrane results in a transepithe lial potential that is more negative on the luminal side. This negative po- ential drives the movement of Na through the paracellular pathway L. Intracellular calcium regulation plays a physiologically important signaling and regulator role in various cellular processes. Cells have developed elaborate mecha nisms to control Ca2+ levels and signals ling in the cytoplasm occurs through a rise in Ca levels, which ac- tivate Ca-binding proteins that transduce the Ca?' signal into a cellular re- onse. Therefore, maintenance of low cytoplasmic Ca levels is required 2. A 20,000-fold concentration gradient exists for Ca*across the plasma mem brane. Furthermore. cells also contain intracellular Ca stores that are se- uestered in the ER, which contains high levels of Ca. Ca'signaling occurs rough a rise in cytoplasmic Ca2+ levels due to either Ca* release from the ER or Ca influx from the extracellular space 3. Cells maintain low lasmic Ca t levels by extruding ca* our using the plasma membrane Ca *-ATPase and the Na-Ca* excha 4. Clestering Ca2" into the Er using the ER Ca? -ATPase. increase their cytoplasmic Ca"* levels in response to primary signa such as hormones and growth factors

Chapter 1: Cell Physiology 7 N (1) The transcellular pathway refers to ion movement through the cell layer, whereas the paracellular pathway refers to ion movement be￾tween cells. (2) The driving force for Cl− movement through the paracellular pathway is the electrical potential generated by the net movement of Na+ (posi￾tive on the basolateral side). (3) Alternatively, if Cl− crosses the epithelium through the transcellular pathway, it usually enters at the apical side through transporters (eg, Cl-HCO3 exchanger, Na+ -K+ -2Cl cotransporter) and leaves the cell at the basolateral side through Cl channels or the K+ -Cl− cotrans￾porter. d. The activity of the Na+ /K+ -ATPase on the basolateral side will result in the transport of K+ ions inside the cell. Therefore, to maintain steady-state ion concentration in the cytosol, the cell must have a mechanism to recycle the pumped K+ . This mechanism involves a variety of K+ channels located on the basolateral membrane. 4. Secretion is conceptually more difficult than absorption, but the same princi￾ples discussed for absorption apply. a. The Na+ /K+ -ATPase on the basolateral membrane pumps Na+ out and K+ into the cell. K+ is recycled back into the extracellular fluid through the ac￾tion of K+ channels on the basolateral membrane. b. The Na+ gradient generated by the Na+ /K+ -ATPase is used to drive the Na+ -K+ -2Cl− (or K+ -Cl− ) cotransporter on the basolateral membrane, re￾sulting in the net transport of Cl− into the cell. c. The increased Cl− concentration inside the cell causes Cl− secretion through Cl− channels on the apical membrane, resulting in net Cl− trans￾port across the epithelial cell layer. d. The combined secretion of Cl− into the lumen (apical side) and efflux of K+ through K+ channels on the basolateral membrane results in a transepithe￾lial potential that is more negative on the luminal side. This negative po￾tential drives the movement of Na+ through the paracellular pathway toward the lumen. L. Intracellular calcium regulation plays a physiologically important signaling and regulator role in various cellular processes. Cells have developed elaborate mecha￾nisms to control Ca2+ levels and signals. 1. Ca2+ signaling in the cytoplasm occurs through a rise in Ca2+ levels, which ac￾tivate Ca2+-binding proteins that transduce the Ca2+ signal into a cellular re￾sponse. Therefore, maintenance of low cytoplasmic Ca2+ levels is required for Ca2+ signaling. 2. A 20,000-fold concentration gradient exists for Ca2+ across the plasma mem￾brane. Furthermore, cells also contain intracellular Ca2+ stores that are se￾questered in the ER, which contains high levels of Ca2+. Ca2+ signaling occurs through a rise in cytoplasmic Ca2+ levels due to either Ca2+ release from the ER or Ca2+ influx from the extracellular space. 3. Cells maintain low cytoplasmic Ca2+ levels by extruding Ca2+ out of the cell using the plasma membrane Ca2+-ATPase and the Na+ -Ca2+ exchanger, or by sequestering Ca2+ into the ER using the ER Ca2+-ATPase. 4. Cells increase their cytoplasmic Ca2+ levels in response to primary signals such as hormones and growth factors. 5506ch01.qxd_ccII 2/17/03 2:08 PM Page 7

8 USMLE Road Map: Physiology 的 a. Once the primary signal is received, Ca" channels on the ER membrane or n the cytos n,releasing Ca into the cytoplasm and transducing the o a cellular response b. Channels on the er membrane that mediate Cat+ release include the inos- tol 1, 4, 5-triphosphate(IP3)receptor and the ryanodine recep c. Ca influx from the extracellular space is mediated by different channel classes, including ligand-gated channels(such as the AChR)and voltage gated channels(such as the Ca+ channels in cardiac muscle) DISEASES ASSOCIATED WITH CALCIUM REGULATORY DEFECTS Malignant hyperthermia is a subclinical disease resulting from a genetic predisposition to react normally to volatile anesthetics such as halothane and muscle relaxants such as carbachol Malignant hyperthermia is due to mutations in the ryanodine receptor leading to an overactive receptor. The mutated ryanodine receptor is especially sensitive to the aforementioned anesthetics, re- ulting in increased Ca- release and sustained muscle contraction. -Under severe conditions, extensive necrosis of muscle cells follows, leading to release of large mounts of k cardia High Ca *levels will also lead to the continuous activation of the ER Ca*-ATPase and muscle contrac- on, resulting in increased heat production and hyperthermia. vigorous exercise could also lead to abnormal muscle contraction in individuals with malignant hy -This condition can be treated with dantrolene, which inhibits the ryanodine receptor. Brody disease is an autosomal recessive mutation in the ER Ca*-ATPase, which leads to exercise- induced impairment of skeletal muscle relaxation. Darier disease is a skin disorder due to mutations in the ER Ca*-ATPase, leading to disruption of he cytoskeleton of skin cells and loss of adhesion between these cells. X-linked congenital stationary night blindness is a recessive disease of the human retina due to mutations in a voltage-gated Ca* channel, leading to defects in glutamate release and neurotrans- mission, which impairs the function of rod and cone cells in the retina. Lambert-Eaton myasthenic syndrome(LEMS) is an autoimmune disease characterized by an in- creased number of LEMS antibodies against voltage-gated Ca* channels, leading to defective neu transmission and weakness of proximal muscles. IlL. Cell Signaling A. Types of Cell Signaling Autocrine signaling involves a secreted substa ng on the same cell 2. Paracrine signaling involves a substance diffusing from the signaling cell that produced it to nearby target cells to elicit a response. For example, the gastrointestinal regulatory peptide somatostatin is produced by d cells in the stomach and diffuses to gastric acid cells to decrease secretion. 3. Endocrine signaling involves a substance secreted by endocrine cells that is transported in the blood to distant target cells to elicit a response. For exam- ple, adrenocorticotropic hormone, which is released from the anterior ary into the blood, stimulates the release of cortisol from the adrenal gla B. Cell Signaling Events 1. A signaling cell produces a signaling molecule termed a ligand or primary ssenger, which binds a receptor associated with a target cell

8 USMLE Road Map: Physiology N a. Once the primary signal is received, Ca2+ channels on the ER membrane or in the cytosol open, releasing Ca2+ into the cytoplasm and transducing the primary signal into a cellular response. b. Channels on the ER membrane that mediate Ca2+ release include the inosi￾tol 1,4,5-triphosphate (IP3) receptor and the ryanodine receptor. c. Ca2+ influx from the extracellular space is mediated by different channel classes, including ligand-gated channels (such as the AChR) and voltage￾gated channels (such as the Ca2+ channels in cardiac muscle). DISEASES ASSOCIATED WITH CALCIUM REGULATORY DEFECTS • Malignant hyperthermia is a subclinical disease resulting from a genetic predisposition to react ab￾normally to volatile anesthetics such as halothane and muscle relaxants such as carbachol. –Malignant hyperthermia is due to mutations in the ryanodine receptor leading to an overactive receptor. The mutated ryanodine receptor is especially sensitive to the aforementioned anesthetics, re￾sulting in increased Ca2+ release and sustained muscle contraction. –Under severe conditions, extensive necrosis of muscle cells follows, leading to release of large amounts of K+ , cardiac arrhythmias, and often-lethal ventricular fibrillation. –High Ca2+ levels will also lead to the continuous activation of the ER Ca2+-ATPase and muscle contrac￾tion, resulting in increased heat production and hyperthermia. –Vigorous exercise could also lead to abnormal muscle contraction in individuals with malignant hy￾perthermia. –This condition can be treated with dantrolene, which inhibits the ryanodine receptor. • Brody disease is an autosomal recessive mutation in the ER Ca2+-ATPase, which leads to exercise￾induced impairment of skeletal muscle relaxation. • Darier disease is a skin disorder due to mutations in the ER Ca2+-ATPase, leading to disruption of the cytoskeleton of skin cells and loss of adhesion between these cells. • X-linked congenital stationary night blindness is a recessive disease of the human retina due to mutations in a voltage-gated Ca2+ channel, leading to defects in glutamate release and neurotrans￾mission, which impairs the function of rod and cone cells in the retina. • Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease characterized by an in￾creased number of LEMS antibodies against voltage-gated Ca2+ channels, leading to defective neu￾rotransmission and weakness of proximal muscles. III. Cell Signaling A. Types of Cell Signaling 1. Autocrine signaling involves a secreted substance acting on the same cell that produced it. 2. Paracrine signaling involves a substance diffusing from the signaling cell that produced it to nearby target cells to elicit a response. For example, the gastrointestinal regulatory peptide somatostatin is produced by D cells in the stomach and diffuses to gastric acid cells to decrease secretion. 3. Endocrine signaling involves a substance secreted by endocrine cells that is transported in the blood to distant target cells to elicit a response. For exam￾ple, adrenocorticotropic hormone, which is released from the anterior pitu￾itary into the blood, stimulates the release of cortisol from the adrenal gland. B. Cell Signaling Events 1. A signaling cell produces a signaling molecule termed a ligand or primary messenger, which binds a receptor associated with a target cell. CLINICAL CORRELATION 5506ch01.qxd_ccII 2/17/03 2:08 PM Page 8