《医学生理学 Medical Physiology》参考教材资料（PDF电子书籍）Uwe Ackermann. PDQ Physiology, 2002, Uwe Ackerman

PDQ PHYSIOLOGY stimulate production of arachidonic acid from membrane phospholipids (see Figure 1-4 Activated G proteins spontaneously return to their resting state Activated G proteins that are linked to intracellular enzymes will inhibit (in the case of G proteins)or promote(in the case of Gs or ga proteins)the intracellular concentration of the second messengers, cAMP, cGMP, dia cylglycerol(DAG), inositol triphosphate(IP,), and Ca Second Messengers These chemicals were named"second"messengers to make it clear that the ligand activating the receptor is the first messenger. The second messengers re intracellular transducers and function to produce cellular responses to extracellular signals The adenylate cyclase system. Formation of cAMP from ATP by the plasma membrane-bound enzyme adenylate cyclase is modulated by both stimulatory and inhibitory receptors(R, and Ri)(see Figure 1-13)and G proteins(Gs and Gi)(see Figure 1-13). Cyclic adenosine monophosphate (cAMP)promotes the activation of protein kinase A(PKA) Protein kinase A exists as two subunits, one regulatory and the other catalytic. Binding of cAMP causes the two subunits to dissociate and the catalytic subunit to become activated so that it is capable of phosphorylating proteins, thereby altering their function and bringing about a biologic action. The most prominent example of this second messenger system and the duality of effects that can be elicited by the same ligand are seen in the action of epinephrine(adrenaline). When it acts on d2-adrenoreceptors, it causes inhibition of cAMP formation; when it acts on pr-adrenoreceptors, it pro- motes cAmp formation The phospholipase C system. As shown in Figure 1-5, phospholipase C cleaves membrane phospholipids so as to yield DAg plus the head portion of the phospholipid. The two most relevant C-type phospholipases are phospholipase CB(PLP-CB), which is attached to the cytosolic side of the plasma membrane, and phospholipase Cy(PLP-Cy), which is a cytosolic enzyme. Phospholipase-CB is activated by ga proteins and, therefore, requires binding and hydrolysis of GTP(Figure 1-14). Phospholipase-Cy is activated by tyrosine kinase-linked receptors and requires (1)ATP hydrolysis for activation and(2) translocation from the cytosol to an attachment point on the plasma membrane. Phosphatidylinositol 4, 5 bisphosphate(PIP2)is the membrane phospholipid that is most important for the phospholipase-C system. Phosphatidylinositol 4, 5-bisphosphate2 is

stimulate production of arachidonic acid from membrane phospholipids (see Figure 1–4). Activated G proteins spontaneously return to their resting state. Activated G proteins that are linked to intracellular enzymes will inhibit (in the case of Gi proteins) or promote (in the case of Gs or Gq proteins) the intracellular concentration of the second messengers, cAMP, cGMP, dia￾cylglycerol (DAG), inositol triphosphate (IP3), and Ca++. Second Messengers These chemicals were named “second” messengers to make it clear that the ligand activating the receptor is the first messenger. The second messengers are intracellular transducers and function to produce cellular responses to extracellular signals. The adenylate cyclase system. Formation of cAMP from ATP by the plasma membrane–bound enzyme adenylate cyclase is modulated by both stimulatory and inhibitory receptors (Rs and Ri) (see Figure 1–13) and G proteins (Gs and Gi) (see Figure 1–13). Cyclic adenosine monophosphate (cAMP) promotes the activation of protein kinase A (PKA). Protein kinase A exists as two subunits, one regulatory and the other catalytic. Binding of cAMP causes the two subunits to dissociate and the catalytic subunit to become activated so that it is capable of phosphorylating proteins, thereby altering their function and bringing about a biologic action. The most prominent example of this second messenger system and the duality of effects that can be elicited by the same ligand are seen in the action of epinephrine (adrenaline). When it acts on α2-adrenoreceptors, it causes inhibition of cAMP formation; when it acts on β1-adrenoreceptors, it pro￾motes cAMP formation. The phospholipase C system. As shown in Figure 1–5, phospholipase C cleaves membrane phospholipids so as to yield DAG plus the head portion of the phospholipid. The two most relevant C-type phospholipases are phospholipase Cβ (PLP-Cβ), which is attached to the cytosolic side of the plasma membrane, and phospholipase Cγ (PLP-Cγ), which is a cytosolic enzyme. Phospholipase-Cβ is activated by Gq proteins and, therefore, requires binding and hydrolysis of GTP (Figure 1–14). Phospholipase-Cγ is activated by tyrosine kinase–linked receptors and requires (1) ATP hydrolysis for activation and (2) translocation from the cytosol to an attachment point on the plasma membrane. Phosphatidylinositol 4,5- bisphosphate (PIP2) is the membrane phospholipid that is most important for the phospholipase-C system. Phosphatidylinositol 4,5-bisphosphate2 is 30 PDQ PHYSIOLOGY

Chapter 1 General Physiologic Processes brane 些(气a ATP PKA CAMP activated PDe s PKA 5′AMP lase system by which the second messenger th stimulatory and inhibitory paths are shown. When a g protein is activated by receptor lig and interaction, its a-subunit replaces the bound GDP molecule with a GTP and the B-y moi ety dissociates, allowing the GTP-ax-subunit to act on the membrane enzyme adenylate cyclase esterases, cAMP activates protein kinase A(PKA) Protein kinase A promotes phosphorylation of a variety of intracellular effectors. a, B, Y=sub units of G protein; ATP=adenosine triphosphate; cAMP= cyclic adenosine monophosphate; 5 AMP=5′ adenosine sphate: G;, Gs inhibitory, stimulatory G protein; GDP= guan sine diphosphate: GTP=guanosine triphosphate; L=ligand; PDE= phosphodiesterase; Ri, Rs cleaved by PLP-CB or PLP-Cy to yield three products: DAG, a small fraction of a cyclic triphosphate, and mostly IP3(see Figure 1-14) Diacylglycerol. Diacylglycerol, formed from phospholipids by the action of the phospholipase C family, is a second messenger in its function as an activator of the protein kinase C(PKC)family. Activated PKCs phospho rylate proteins and promote, among others, Ca*t-ATPase activity, gene expression and activation of cell proliferation, ion channels, and exocyto- sis. They also provide negative feedback by suppressing phospholipase C activation and down-regulating receptors of the adenylate cyclase cascade suggested in Figure 1-5, DAG can be cleaved by phospholipase A2to yield arachidonic acid(AA). Arachidonic acid can be metabolized by five eparate pathways to yield the prostaglandins(the cyclooxygenase pathway) the leukotrienes(the 5-lipoxigenase pathway), and other eicosanoids(from the cytochrome P-450 mono-oxygenase pathway or the 15-lipoxigenase and

cleaved by PLP-Cβ or PLP-Cγ to yield three products: DAG, a small fraction of a cyclic triphosphate, and mostly IP3 (see Figure 1–14). Diacylglycerol. Diacylglycerol, formed from phospholipids by the action of the phospholipase C family, is a second messenger in its function as an activator of the protein kinase C (PKC) family. Activated PKCs phospho￾rylate proteins and promote, among others, Ca++–ATPase activity, gene expression and activation of cell proliferation, ion channels, and exocyto￾sis. They also provide negative feedback by suppressing phospholipase C activation and down-regulating receptors of the adenylate cyclase cascade. As suggested in Figure 1–5, DAG can be cleaved by phospholipase A2 to yield arachidonic acid (AA). Arachidonic acid can be metabolized by five separate pathways to yield the prostaglandins (the cyclooxygenase pathway), the leukotrienes(the 5-lipoxigenase pathway), and other eicosanoids(from the cytochrome P-450 mono-oxygenase pathway or the 15-lipoxigenase and Chapter 1 General Physiologic Processes 31 Rs L L L L L L L L GDP GDP Gs Gi Ri α α β β γ γ ADENYLATE CYCLASE plasma membrane cAMP ATP + - PKA activated PKA + PDE’s + GTP GTP 5' AMP Figure 1–13 The adenylate cyclase system by which the second messenger cAMP is formed. Both stimulatory and inhibitory paths are shown. When a G protein is activated by receptor-lig￾and interaction, its -subunit replaces the bound GDP molecule with a GTP and the - moi￾ety dissociates, allowing the GTP--subunit to act on the membrane enzyme adenylate cyclase. Before it is rapidly metabolized by phosphodiesterases, cAMP activates protein kinase A (PKA). Protein kinase A promotes phosphorylation of a variety of intracellular effectors. , ,  = sub￾units of G protein; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; 5 AMP = 5 adenosine monophosphate; Gi, Gs = inhibitory, stimulatory G protein; GDP = guano￾sine diphosphate; GTP = guanosine triphosphate; L = ligand; PDE = phosphodiesterase; Ri, Rs = inhibitory, stimulatory receptor.

PDQ PHYSIOLOGY plasma membrane E eOSPHOLPASE C). PI DAG PKO e 1-14 The phospholipase C system by which the second messengers diacylglycerol phosphatidyinositol 1, 4, 5-trisphosphate(IP3), and Ca*are formed. Binding of al to its receptor activates one of the Ga proteins and that activates membrane-associated ph pase CB. Activated phospholipase CB hydrolyzes the minor membrane phospholipid phosphatidylinositol 4, 5-bisphosphate(PIP2)to yield DAG, and inositol 1, 4, 5-trisphosphate(IP3l binds and activates a Ca** release channel in the endoplasmic reticulum; it also increases men ane Ca*conductance. This latter action might be due to an IP3 metabolite Diacylglycerol acti ates protein kinase C(PKC) and can be cleaved by phospholipase A2(PLA )to yield arachidonic 12-lipoxigenase pathways in platelets and leukocytes). All of these AA etabolites have important physiologic actions. Inositol 1, 4, 5-trisphosphate and metabolites. The metabolic fate of IP3 is that it eventually becomes inositol. This happens in several steps, the first of which is mostly a dephosphorylation that yields inositol 1, 4-bisphos phate. However, there is an alternative path whose first step is phosphor lation of IP, to yield inositol 1, 3, 4, 5-tetrakisphosphate(IP4). Inositol 1, 4, 5- trisphosphate operates by a receptor-mediated mechanism to elevate cytosolic [Ca*(see Figure 1-14). The IP3 receptor is similar to the ryan odine receptor(Ca*+release channel) found in the sarcoplasmic reticulum muscle. Inositol 1, 3, 4, 5-tetrakisphosphate may enhance Ca influx from the extracellular space by opening a membrane Ca** channel. Ionized calcium(Ca**). Ionized calcium acts as an intracellular second messenger in several cellular responses. It is released from intracellular stores and brought in from the extracellular space down a steep electro chemical gradient when the Ca** channels are oper

12-lipoxigenase pathways in platelets and leukocytes). All of these AA metabolites have important physiologic actions. Inositol 1,4,5-trisphosphate and metabolites. The metabolic fate of IP3 is that it eventually becomes inositol. This happens in several steps, the first of which is mostly a dephosphorylation that yields inositol 1,4-bisphos￾phate. However, there is an alternative path whose first step is phosphory￾lation of IP3 to yield inositol 1,3,4,5-tetrakisphosphate (IP4). Inositol 1,4,5- trisphosphate operates by a receptor-mediated mechanism to elevate cytosolic [Ca++] (see Figure 1–14). The IP3 receptor is similar to the ryan￾odine receptor (Ca++ release channel) found in the sarcoplasmic reticulum of cardiac muscle. Inositol 1,3,4,5-tetrakisphosphate may enhance Ca++ influx from the extracellular space by opening a membrane Ca++ channel. Ionized calcium (Ca++). Ionized calcium acts as an intracellular second messenger in several cellular responses. It is released from intracellular stores and brought in from the extracellular space down a steep electro￾chemical gradient when the Ca++ channels are open. 32 PDQ PHYSIOLOGY R L L L GDP Gq α β plasma membrane + activated PKC PHOSPHOLIPASE Cβ activated PIP2 + DAG IP3 Ca++ + Ca++ PKC Arachidonic Acid PLA2 Ca++ GTP γ Figure 1–14 The phospholipase C system by which the second messengers diacylglycerol (DAG) phosphatidyinositol 1,4,5-trisphosphate (IP3), and Ca++ are formed. Binding of a ligand (L), to its receptor activates one of the Gq proteins and that activates membrane-associated phos￾pholipase C. Activated phospholipase C hydrolyzes the minor membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) to yield DAG, and inositol 1,4,5-trisphosphate (IP3) binds and activates a Ca++ release channel in the endoplasmic reticulum; it also increases mem￾brane Ca++ conductance. This latter action might be due to an IP3 metabolite. Diacylglycerol acti￾vates protein kinase C (PKC) and can be cleaved by phospholipase A2 (PLA2) to yield arachidonic acid

Chapter 1 General Physiologic Processes Ca++ stores: The main intracellular Ca++ stores are the mitochondria and the endoplasmic reticulum, and it is the latter that is most impor tant for signaling functions. Release from stores occurs by one of two mechanisms: ryanodine receptors or IP, receptors. Both may be present in the same cell. After release, the stores are refilled by a Ca*t-ATPase Cat+ influx: There is both a voltage gradient and a steep concentra tion gradient** for Cat*+ to enter cells provided that Ca* channels are open. It has been hypothesized that IP or IP, or one of its isomers can modulate conductivity in membrane Ca** channels Ionized calcium that has been released into the cytosol binds to intra- cellular receptors such as calmodulin(most mammalian cells)or tro- ponin C (striated muscle cells). The Ca++-calmodulin complex controls a large number of enzymes(including phosphodiesterases),transporters,ion channels(including Ca* channels), and calmodulin-dependent kinases that exert their biologic effects by way of protein phosphorylation Cyclic GMP. Cyclic GMP is formed from GTP by the enzyme guanylate cyclase. Activated guanylate cyclase can also accept ATP to form cAMP when GTP is not available. Guanylate cyclase exists in two forms articulate and soluble Particulate guanylate cyclase(pGC). This form is associated with mem- branes and is present in the plasma membrane as well as the membranes of ER, Golgi apparatus, and nucleus. It is part of a complex that spans the embrane only once and is located on the intracellular end, near the car boxy terminus(Figure 1-15). The amino end is on the extracellular side and includes the receptor Particulate guanylate cyclase is activated by a variety of peptides, including the atrial natriuretic peptides(ANP) Soluble guanylate cyclase(sGC). This is found in the cytosol and includes a heme group(see Figure 1-15). It is activated by several agents, including nitric oxide(NO), organic nitrates, and free radicals. It is inhibited by sev ral agents, including those that contain ferrous iron(fe++)(hemoglobin and The cellular effects of cGMP are mediated by three types of intracellu lar proteins. They are 1. cGMP-sensitive ion channels such as (a) the nonselective cation chan nel in rod photoreceptor cells of the retina and(b) the amiloride- Intracellular Cat+ concentration is normally near 10-7M, whereas extracellular [Ca*I s about2×10-3M

• Ca++ stores: The main intracellular Ca++ stores are the mitochondria and the endoplasmic reticulum, and it is the latter that is most impor￾tant for signaling functions. Release from stores occurs by one of two mechanisms: ryanodine receptors or IP3 receptors. Both may be present in the same cell. After release, the stores are refilled by a Ca++–ATPase. • Ca++ influx: There is both a voltage gradient and a steep concentra￾tion gradient** for Ca++ to enter cells provided that Ca++ channels are open. It has been hypothesized that IP4 or IP3 or one of its isomers can modulate conductivity in membrane Ca++ channels. Ionized calcium that has been released into the cytosol binds to intra￾cellular receptors such as calmodulin (most mammalian cells) or tro￾ponin C (striated muscle cells). The Ca++–calmodulin complex controls a large number of enzymes (including phosphodiesterases), transporters, ion channels (including Ca++ channels), and calmodulin-dependent kinases that exert their biologic effects by way of protein phosphorylation. Cyclic GMP. Cyclic GMP is formed from GTP by the enzyme guanylate cyclase. Activated guanylate cyclase can also accept ATP to form cAMP when GTP is not available. Guanylate cyclase exists in two forms: particulate and soluble. Particulate guanylate cyclase (pGC). This form is associated with mem￾branes and is present in the plasma membrane as well as the membranes of ER, Golgi apparatus, and nucleus. It is part of a complex that spans the membrane only once and is located on the intracellular end, near the car￾boxy terminus (Figure 1–15). The amino end is on the extracellular side and includes the receptor. Particulate guanylate cyclase is activated by a variety of peptides, including the atrial natriuretic peptides (ANP). Soluble guanylate cyclase (sGC). This is found in the cytosol and includes a heme group (see Figure 1–15). It is activated by several agents, including nitric oxide (NO), organic nitrates, and free radicals. It is inhibited by sev￾eral agents, including those that contain ferrous iron (Fe++) (hemoglobin and myoglobin). The cellular effects of cGMP are mediated by three types of intracellu￾lar proteins. They are 1. cGMP-sensitive ion channels such as (a) the nonselective cation chan￾nel in rod photoreceptor cells of the retina and (b) the amiloride￾Chapter 1 General Physiologic Processes 33 **Intracellular Ca++ concentration is normally near 10–7 M, whereas extracellular [Ca++] is about 2 10–3 M.

PDQ PHYSIOLOGY 口 Ligand La cytosol CGMP Guanylate Cyclase mbrane cytosol CGMP Soluble Figure 1-15 Synthesis of cGMP is catalyzed by two types of guanylate cyclase: A, Particu- te guanylate cyclase is part of the cytosolic domain of the plasma membrane receptors of lin peptide hormones. Ligand binding to such guanylate cyclase and causes formation of cGMP. B, Soluble guanylate cyclases are activate by nitric oxide(NO). These guanylate cyclases are heterodimers and include a bound heme mol ecule that interacts with both subunits. Nitric oxide binding to the heme leads to a conforma sensitive Na* channel of the inner medullary collecting duct of the 2. CGMP-dependent protein kinases, such as myosin light chain kinase in smooth muscle: and 3. CGMP-regulated phosphodiesterases like phosphodiesterase III(PDE III). Cyclic GMP inhibits and thereby inhibits breakdown of CAMP by PDE III. In this way, elevation of cGMP leads to elevation of caMp Like CAMP, CGMP is inactivated by phosphodiesterases. One such diesterase, phosphodiesterase type 5, has gained recent prominence because it is inhibited by sildenaphil(sold commercially as Viagra"). Such inhibition prolongs the cGMP-mediated vasodilatation that causes penil erection

sensitive Na+ channel of the inner medullary collecting duct of the nephron; 2. cGMP-dependent protein kinases, such as myosin light chain kinase in smooth muscle; and 3. cGMP-regulated phosphodiesterases like phosphodiesterase III (PDE III). Cyclic GMP inhibits PDE III and thereby inhibits breakdown of cAMP by PDE III. In this way, elevation of cGMP leads to elevation of cAMP. Like cAMP, cGMP is inactivated by phosphodiesterases. One such diesterase, phosphodiesterase type 5, has gained recent prominence because it is inhibited by sildenaphil (sold commercially as “Viagra”). Such inhibition prolongs the cGMP-mediated vasodilatation that causes penile erection. 34 PDQ PHYSIOLOGY plasma membrane Ligand A) GTP cytosol plasma membrane Ligand GTP cytosol P cGMP i Pi Particulate Guanylate Cyclase B) plasma membrane cytosol plasma membrane GTP cytosol cGMP Pi Pi Soluble Guanylate Cyclase N N N N Fe NO N N N N Fe GTP NO Figure 1–15 Synthesis of cGMP is catalyzed by two types of guanylate cyclase: A, Particu￾late guanylate cyclase is part of the cytosolic domain of the plasma membrane receptors of cer￾tain peptide hormones. Ligand binding to such receptors promotes activation of particulate guanylate cyclase and causes formation of cGMP. B, Soluble guanylate cyclases are activated by nitric oxide (NO). These guanylate cyclases are heterodimers and include a bound heme mol￾ecule that interacts with both subunits. Nitric oxide binding to the heme leads to a conforma￾tional change in the enzyme subunits and stimulates catalytic activity